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  1. Valeria Crippa, Maria Elena Cicardi, Nandini Ramesh, Samuel J Seguin, Massimo Ganassi, Ilaria Bigi, Chiara Diacci, Elena Zelotti, Madina Baratashvili, Jenna M Gregory, Christopher M Dobson, Cristina Cereda, Udai Bhan Pandey, Angelo Poletti and Serena Carra.
    The chaperone HSPB8 reduces the accumulation of truncated TDP-43 species in cells and protects against TDP-43-mediated toxicity.. Human molecular genetics, July 2016.
    Abstract Aggregation of TAR-DNA-binding protein 43 (TDP-43) and of its fragments TDP-25 and TDP-35 occurs in amyotrophic lateral sclerosis (ALS). TDP-25 and TDP-35 act as seeds for TDP-43 aggregation, altering its function and exerting toxicity. Thus, inhibition of TDP-25 and TDP-35 aggregation and promotion of their degradation may protect against cellular damage. Upregulation of HSPB8 is one possible approach for this purpose, since this chaperone promotes the clearance of an ALS associated fragments of TDP-43 and is upregulated in the surviving motor neurones of transgenic ALS mice and human patients. We report that overexpression of HSPB8 in immortalized motor neurones decreased the accumulation of TDP-25 and TDP-35 and that protection against mislocalized/truncated TDP-43 was observed for HSPB8 in Drosophila melanogaster Overexpression of HSP67Bc, the functional ortholog of human HSPB8, suppressed the eye degeneration caused by the cytoplasmic accumulation of a TDP-43 variant with a mutation in the nuclear localization signal (TDP-43-NLS). TDP-43-NLS accumulation in retinal cells was counteracted by HSP67Bc overexpression. According with this finding, downregulation of HSP67Bc increased eye degeneration, an effect that is consistent with the accumulation of high molecular weight TDP-43 species and ubiquitinated proteins. Moreover, we report a novel Drosophila model expressing TDP-35, and show that while TDP-43 and TDP-25 expression in the fly eyes causes a mild degeneration, TDP-35 expression leads to severe neurodegeneration as revealed by pupae lethality; the latter effect could be rescued by HSP67Bc overexpression. Collectively, our data demonstrate that HSPB8 upregulation mitigates TDP-43 fragment mediated toxicity, in mammalian neuronal cells and flies.
    URL, DOI BibTeX

    @article{Crippa2016,
    	abstract = "Aggregation of TAR-DNA-binding protein 43 (TDP-43) and of its fragments TDP-25 and TDP-35 occurs in amyotrophic lateral sclerosis (ALS). TDP-25 and TDP-35 act as seeds for TDP-43 aggregation, altering its function and exerting toxicity. Thus, inhibition of TDP-25 and TDP-35 aggregation and promotion of their degradation may protect against cellular damage. Upregulation of HSPB8 is one possible approach for this purpose, since this chaperone promotes the clearance of an ALS associated fragments of TDP-43 and is upregulated in the surviving motor neurones of transgenic ALS mice and human patients. We report that overexpression of HSPB8 in immortalized motor neurones decreased the accumulation of TDP-25 and TDP-35 and that protection against mislocalized/truncated TDP-43 was observed for HSPB8 in Drosophila melanogaster Overexpression of HSP67Bc, the functional ortholog of human HSPB8, suppressed the eye degeneration caused by the cytoplasmic accumulation of a TDP-43 variant with a mutation in the nuclear localization signal (TDP-43-NLS). TDP-43-NLS accumulation in retinal cells was counteracted by HSP67Bc overexpression. According with this finding, downregulation of HSP67Bc increased eye degeneration, an effect that is consistent with the accumulation of high molecular weight TDP-43 species and ubiquitinated proteins. Moreover, we report a novel Drosophila model expressing TDP-35, and show that while TDP-43 and TDP-25 expression in the fly eyes causes a mild degeneration, TDP-35 expression leads to severe neurodegeneration as revealed by pupae lethality; the latter effect could be rescued by HSP67Bc overexpression. Collectively, our data demonstrate that HSPB8 upregulation mitigates TDP-43 fragment mediated toxicity, in mammalian neuronal cells and flies.",
    	author = "Crippa, Valeria and Cicardi, Maria Elena and Ramesh, Nandini and Seguin, Samuel J and Ganassi, Massimo and Bigi, Ilaria and Diacci, Chiara and Zelotti, Elena and Baratashvili, Madina and Gregory, Jenna M and Dobson, Christopher M and Cereda, Cristina and Pandey, Udai Bhan and Poletti, Angelo and Carra, Serena",
    	doi = "10.1093/hmg/ddw232",
    	issn = "1460-2083",
    	journal = "Human molecular genetics",
    	month = "jul",
    	pmid = 27466192,
    	title = "{The chaperone HSPB8 reduces the accumulation of truncated TDP-43 species in cells and protects against TDP-43-mediated toxicity.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/27466192",
    	year = 2016
    }
    
  2. André-Patrick Arrigo and Benjamin Gibert.
    Protein interactomes of three stress inducible small heat shock proteins: HspB1, HspB5 and HspB8.. International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group 29(5):409–22, August 2013.
    Abstract PURPOSE: The recent discoveries in the field of human small heat shock proteins (sHSPs) clearly point to the important roles played by these adenosine triphosphate (ATP)-independent chaperones in the regulation of a large spectrum of vital cellular processes and in pathological diseases. These proteins are therefore considered as very attractive therapeutic targets. AIMS: To understand the functions of the stress-inducible members of the sHSP family, HspB1, HspB5 and HspB8, and be able to therapeutically modulate their activities, researchers are faced with the complex oligomerisation and phosphorylation properties of these proteins and with their ability to interact with each other and with specific protein targets. Here, we have integrated, in a functionally orientated way, the up-to-date literature data concerning HspB1, HspB5 and HspB8 protein interactions which reflect their numerous crucial cellular functions. We also present data supporting the idea that specific phospho-oligomeric domains of HspB1 are involved in the interaction with particular client proteins. CONCLUSIONS: More information concerning the interactions between client protein targets and sHSPs or the multiple combinatorial chimeric oligomeric complexes formed by different sHSPs are urgently required to elaborate a comprehensive sHSPs protein interactome and propose efficient and pathology-specific therapeutic approaches.
    URL, DOI BibTeX

    @article{Arrigo2013,
    	abstract = "PURPOSE: The recent discoveries in the field of human small heat shock proteins (sHSPs) clearly point to the important roles played by these adenosine triphosphate (ATP)-independent chaperones in the regulation of a large spectrum of vital cellular processes and in pathological diseases. These proteins are therefore considered as very attractive therapeutic targets. AIMS: To understand the functions of the stress-inducible members of the sHSP family, HspB1, HspB5 and HspB8, and be able to therapeutically modulate their activities, researchers are faced with the complex oligomerisation and phosphorylation properties of these proteins and with their ability to interact with each other and with specific protein targets. Here, we have integrated, in a functionally orientated way, the up-to-date literature data concerning HspB1, HspB5 and HspB8 protein interactions which reflect their numerous crucial cellular functions. We also present data supporting the idea that specific phospho-oligomeric domains of HspB1 are involved in the interaction with particular client proteins. CONCLUSIONS: More information concerning the interactions between client protein targets and sHSPs or the multiple combinatorial chimeric oligomeric complexes formed by different sHSPs are urgently required to elaborate a comprehensive sHSPs protein interactome and propose efficient and pathology-specific therapeutic approaches.",
    	author = "Arrigo, Andr{\'{e}}-Patrick and Gibert, Benjamin",
    	doi = "10.3109/02656736.2013.792956",
    	issn = "1464-5157",
    	journal = "International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group",
    	keywords = "Animals,HSP27 Heat-Shock Proteins,HSP27 Heat-Shock Proteins: metabolism,Heat-Shock Proteins,Heat-Shock Proteins: metabolism,Humans,Protein-Serine-Threonine Kinases,Protein-Serine-Threonine Kinases: metabolism,Signal Transduction,alpha-Crystallin B Chain,alpha-Crystallin B Chain: metabolism",
    	month = "aug",
    	number = 5,
    	pages = "409--22",
    	pmid = 23697380,
    	title = "{Protein interactomes of three stress inducible small heat shock proteins: HspB1, HspB5 and HspB8.}",
    	url = "http://www.mendeley.com/research/protein-interactomes-three-stress-inducible-small-heat-shock-proteins-hspb1-hspb5-hspb8/",
    	volume = 29,
    	year = 2013
    }
    
  3. Julie Acunzo, Maria Katsogiannou and Palma Rocchi.
    Small heat shock proteins HSP27 (HspB1), $\alpha$B-crystallin (HspB5) and HSP22 (HspB8) as regulators of cell death.. The international journal of biochemistry & cell biology 44(10):1622–31, October 2012.
    Abstract Hsp27, $\alpha$B-crystallin and HSP22 are ubiquitous small heat shock proteins (sHsp) whose expression is induced in response to a wide variety of unfavorable physiological and environmental conditions. These sHsp protect cells from otherwise lethal conditions mainly by their involvement in cell death pathways such as necrosis, apoptosis or autophagy. At a molecular level, the mechanisms accounting for sHsp functions in cell death are (1) prevention of denatured proteins aggregation, (2) regulation of caspase activity, (3) regulation of the intracellular redox state, (4) function in actin polymerization and cytoskeleton integrity and (5) proteasome-mediated degradation of selected proteins. In cancer cells, these sHsp are often overexpressed and associated with increased tumorigenicity, cancer cells metastatic potential and resistance to chemotherapy. Altogether, these properties suggest that Hsp27, $\alpha$B-crystallin and Hsp22 are appropriate targets for modulating cell death pathways. In the present, we briefly review recent reports showing molecular evidence of cell death regulation by these sHsp and co-chaperones. This article is part of a Directed Issue entitled: Small HSPs in physiology and pathology.
    URL, DOI BibTeX

    @article{Acunzo2012,
    	abstract = "Hsp27, $\alpha$B-crystallin and HSP22 are ubiquitous small heat shock proteins (sHsp) whose expression is induced in response to a wide variety of unfavorable physiological and environmental conditions. These sHsp protect cells from otherwise lethal conditions mainly by their involvement in cell death pathways such as necrosis, apoptosis or autophagy. At a molecular level, the mechanisms accounting for sHsp functions in cell death are (1) prevention of denatured proteins aggregation, (2) regulation of caspase activity, (3) regulation of the intracellular redox state, (4) function in actin polymerization and cytoskeleton integrity and (5) proteasome-mediated degradation of selected proteins. In cancer cells, these sHsp are often overexpressed and associated with increased tumorigenicity, cancer cells metastatic potential and resistance to chemotherapy. Altogether, these properties suggest that Hsp27, $\alpha$B-crystallin and Hsp22 are appropriate targets for modulating cell death pathways. In the present, we briefly review recent reports showing molecular evidence of cell death regulation by these sHsp and co-chaperones. This article is part of a Directed Issue entitled: Small HSPs in physiology and pathology.",
    	author = "Acunzo, Julie and Katsogiannou, Maria and Rocchi, Palma",
    	doi = "10.1016/j.biocel.2012.04.002",
    	issn = "1878-5875",
    	journal = "The international journal of biochemistry {\&} cell biology",
    	keywords = "Animals,Apoptosis Regulatory Proteins,Apoptosis Regulatory Proteins: genetics,Apoptosis Regulatory Proteins: metabolism,Apoptosis Regulatory Proteins: physiology,Cell Death,Gene Expression,HSP27 Heat-Shock Proteins,HSP27 Heat-Shock Proteins: genetics,HSP27 Heat-Shock Proteins: metabolism,HSP27 Heat-Shock Proteins: physiology,Heat-Shock Proteins,Heat-Shock Proteins: genetics,Heat-Shock Proteins: metabolism,Heat-Shock Proteins: physiology,Humans,Organ Specificity,Protein-Serine-Threonine Kinases,Protein-Serine-Threonine Kinases: genetics,Protein-Serine-Threonine Kinases: metabolism,Protein-Serine-Threonine Kinases: physiology,alpha-Crystallin B Chain,alpha-Crystallin B Chain: genetics,alpha-Crystallin B Chain: metabolism,alpha-Crystallin B Chain: physiology",
    	month = "oct",
    	number = 10,
    	pages = "1622--31",
    	pmid = 22521623,
    	title = "{Small heat shock proteins HSP27 (HspB1), $\alpha$B-crystallin (HspB5) and HSP22 (HspB8) as regulators of cell death.}",
    	url = "http://www.mendeley.com/research/small-heat-shock-proteins-hsp27-hspb1-bcrystallin-hspb5-hsp22-hspb8-regulators-cell-death/",
    	volume = 44,
    	year = 2012
    }
    
  4. Joy Irobi, Anne Holmgren, Vicky De Winter, Bob Asselbergh, Jan Gettemans, Dirk Adriaensen, Chantal Ceuterick-de Groote, Rudy Van Coster, Peter De Jonghe and Vincent Timmerman.
    Mutant HSPB8 causes protein aggregates and a reduced mitochondrial membrane potential in dermal fibroblasts from distal hereditary motor neuropathy patients.. Neuromuscular disorders : NMD 22(8):699–711, August 2012.
    Abstract Missense mutations in the small heat shock protein HSPB8 cause distal hereditary motor neuropathy (dHMN) and axonal Charcot-Marie-Tooth disease (CMT2L). We previously demonstrated that, despite the ubiquitous expression of HSPB8, motor neurons appear to be predominantly affected by HSPB8 mutations. Here, we studied the effect of mutant HSPB8 in primary fibroblast cultures derived from dHMN patients' skin biopsy. In early passage cultures, we observed in all patients' fibroblasts HSPB8 protein aggregates that were not detected in control cells. After applying heat shock stress on the patients' early passage cultured cells, the protein aggregates coalesced into larger formations, while in control cells a homogenous upregulation of HSPB8 protein expression was seen. We also found a reduction in the mitochondrial membrane potential in the early passage cultures. After three months in culture, the number of cells with aggregates had become indistinguishable from that in controls and the mitochondrial membrane potential had returned to normal. These results emphasize the possible drawbacks of using patients' non-neuronal cells to study neuropathological disease mechanisms.
    URL, DOI BibTeX

    @article{Irobi2012,
    	abstract = "Missense mutations in the small heat shock protein HSPB8 cause distal hereditary motor neuropathy (dHMN) and axonal Charcot-Marie-Tooth disease (CMT2L). We previously demonstrated that, despite the ubiquitous expression of HSPB8, motor neurons appear to be predominantly affected by HSPB8 mutations. Here, we studied the effect of mutant HSPB8 in primary fibroblast cultures derived from dHMN patients' skin biopsy. In early passage cultures, we observed in all patients' fibroblasts HSPB8 protein aggregates that were not detected in control cells. After applying heat shock stress on the patients' early passage cultured cells, the protein aggregates coalesced into larger formations, while in control cells a homogenous upregulation of HSPB8 protein expression was seen. We also found a reduction in the mitochondrial membrane potential in the early passage cultures. After three months in culture, the number of cells with aggregates had become indistinguishable from that in controls and the mitochondrial membrane potential had returned to normal. These results emphasize the possible drawbacks of using patients' non-neuronal cells to study neuropathological disease mechanisms.",
    	author = "Irobi, Joy and Holmgren, Anne and {De Winter}, Vicky and Asselbergh, Bob and Gettemans, Jan and Adriaensen, Dirk and {Ceuterick-de Groote}, Chantal and {Van Coster}, Rudy and {De Jonghe}, Peter and Timmerman, Vincent",
    	doi = "10.1016/j.nmd.2012.04.005",
    	issn = "1873-2364",
    	journal = "Neuromuscular disorders : NMD",
    	keywords = "Adult,Aged,Apoptosis,Axons,Axons: pathology,Biological Markers,Biological Markers: metabolism,Biopsy,Cells, Cultured,Female,Fibroblasts,Fibroblasts: pathology,Fibroblasts: physiology,Heat-Shock Proteins,Heat-Shock Proteins: genetics,Humans,Male,Membrane Potential, Mitochondrial,Membrane Potential, Mitochondrial: physiology,Middle Aged,Motor Neuron Disease,Motor Neuron Disease: pathology,Motor Neuron Disease: physiopathology,Mutation, Missense,Mutation, Missense: genetics,Protein Binding,Protein-Serine-Threonine Kinases,Protein-Serine-Threonine Kinases: genetics,Proteins,Proteins: metabolism,Skin,Skin: pathology",
    	month = "aug",
    	number = 8,
    	pages = "699--711",
    	pmid = 22595202,
    	title = "{Mutant HSPB8 causes protein aggregates and a reduced mitochondrial membrane potential in dermal fibroblasts from distal hereditary motor neuropathy patients.}",
    	url = "http://www.mendeley.com/research/mutant-hspb8-causes-protein-aggregates-reduced-mitochondrial-membrane-potential-dermal-fibroblasts-d/",
    	volume = 22,
    	year = 2012
    }
    
  5. Mathieu Nivon, Michel Abou-Samra, Emma Richet, Boris Guyot, André-Patrick Arrigo and Carole Kretz-Remy.
    NF-$\kappa$B regulates protein quality control after heat stress through modulation of the BAG3-HspB8 complex.. Journal of cell science 125(Pt 5):1141–51, March 2012.
    Abstract We previously found that the NF-$\kappa$B transcription factor is activated during the recovery period after heat shock; moreover, we demonstrated that NF-$\kappa$B is essential for cell survival after heat shock by activating autophagy, a mechanism that probably helps the cell to cope with hyperthermic stress through clearance of damaged proteins. In this study, we analyze the involvement of NF-$\kappa$B in basal and heat-stress-induced protein quality control, by comparing the level of multiubiquitylated and/or aggregated proteins, and proteasome and autophagic activity in NF-$\kappa$B-competent and NF-$\kappa$B-incompetent cells. We show that NF-$\kappa$B has only a minor role in basal protein quality control, where it modulates autophagosome maturation. By contrast, NF-$\kappa$B is shown to be a key player in protein quality control after hyperthermia. Indeed, NF-$\kappa$B-incompetent cells show highly increased levels of multiubiquitylated and/or aggregated proteins and aggresome clearance defects; a phenotype that disappears when NF-$\kappa$B activity is restored to normal. We demonstrate that during heat shock recovery NF-$\kappa$B activates selective removal of misfolded or aggregated proteins–a process also called 'aggrephagy'–by controlling the expression of BAG3 and HSPB8 and by modulating the level of the BAG3-HspB8 complex. Thus NF-$\kappa$B-mediated increase in the level of the BAG3-HspB8 complex leads to upregulation of aggrephagy and clearance of irreversibly damaged proteins and might increase cell survival in conditions of hyperthermia.
    URL, DOI BibTeX

    @article{Nivon2012,
    	abstract = "We previously found that the NF-$\kappa$B transcription factor is activated during the recovery period after heat shock; moreover, we demonstrated that NF-$\kappa$B is essential for cell survival after heat shock by activating autophagy, a mechanism that probably helps the cell to cope with hyperthermic stress through clearance of damaged proteins. In this study, we analyze the involvement of NF-$\kappa$B in basal and heat-stress-induced protein quality control, by comparing the level of multiubiquitylated and/or aggregated proteins, and proteasome and autophagic activity in NF-$\kappa$B-competent and NF-$\kappa$B-incompetent cells. We show that NF-$\kappa$B has only a minor role in basal protein quality control, where it modulates autophagosome maturation. By contrast, NF-$\kappa$B is shown to be a key player in protein quality control after hyperthermia. Indeed, NF-$\kappa$B-incompetent cells show highly increased levels of multiubiquitylated and/or aggregated proteins and aggresome clearance defects; a phenotype that disappears when NF-$\kappa$B activity is restored to normal. We demonstrate that during heat shock recovery NF-$\kappa$B activates selective removal of misfolded or aggregated proteins--a process also called 'aggrephagy'--by controlling the expression of BAG3 and HSPB8 and by modulating the level of the BAG3-HspB8 complex. Thus NF-$\kappa$B-mediated increase in the level of the BAG3-HspB8 complex leads to upregulation of aggrephagy and clearance of irreversibly damaged proteins and might increase cell survival in conditions of hyperthermia.",
    	author = "Nivon, Mathieu and Abou-Samra, Michel and Richet, Emma and Guyot, Boris and Arrigo, Andr{\'{e}}-Patrick and Kretz-Remy, Carole",
    	doi = "10.1242/jcs.091041",
    	issn = "1477-9137",
    	journal = "Journal of cell science",
    	keywords = "Adaptor Proteins, Signal Transducing,Adaptor Proteins, Signal Transducing: metabolism,Autophagy,Autophagy: physiology,Cell Line, Tumor,Cell Survival,HeLa Cells,Heat-Shock Proteins,Heat-Shock Proteins: metabolism,Heat-Shock Response,Heat-Shock Response: physiology,Humans,NF-kappa B,NF-kappa B: genetics,NF-kappa B: metabolism,Protein Folding,Protein-Serine-Threonine Kinases,Protein-Serine-Threonine Kinases: metabolism,Transcription Factor RelA,Transcription Factor RelA: deficiency,Transcription Factor RelA: genetics,Transcription Factor RelA: metabolism,Ubiquitination",
    	month = "mar",
    	number = "Pt 5",
    	pages = "1141--51",
    	pmid = 22302993,
    	title = "{NF-$\kappa$B regulates protein quality control after heat stress through modulation of the BAG3-HspB8 complex.}",
    	url = "http://www.mendeley.com/research/nfb-regulates-protein-quality-control-after-heat-stress-through-modulation-bag3hspb8-complex/",
    	volume = 125,
    	year = 2012
    }
    
  6. Noelia García-Lax, Laura Tomás-Roca and Faustino Marín.
    Developmental Expression Pattern of Hspb8 mRNA in the Mouse Brain: Analysis Through Online Databases. The Anatomical Record: Advances in Integrative Anatomy and Evolutionary Biology 295(3):492–503, March 2012.
    URL, DOI BibTeX

    @article{Garcia-Lax2012,
    	author = "Garc{\'{i}}a-Lax, Noelia and Tom{\'{a}}s-Roca, Laura and Mar{\'{i}}n, Faustino",
    	doi = "10.1002/ar.21539",
    	issn = 19328486,
    	journal = "The Anatomical Record: Advances in Integrative Anatomy and Evolutionary Biology",
    	month = "mar",
    	number = 3,
    	pages = "492--503",
    	title = "{Developmental Expression Pattern of Hspb8 mRNA in the Mouse Brain: Analysis Through Online Databases}",
    	url = "http://www.mendeley.com/research/developmental-expression-pattern-hspb8-mrna-mouse-brain-analysis-through-online-databases/",
    	volume = 295,
    	year = 2012
    }
    
  7. K Seidel, J Vinet, W F A Dunnen, E R Brunt, M Meister, A Boncoraglio, M P Zijlstra, H W G M Boddeke, U Rüb, H H Kampinga and S Carra.
    The HSPB8-BAG3 chaperone complex is upregulated in astrocytes in the human brain affected by protein aggregation diseases.. Neuropathology and applied neurobiology 38(1):39–53, February 2012.
    Abstract AIMS: HSPB8 is a small heat shock protein that forms a complex with the co-chaperone BAG3. Overexpression of the HSPB8-BAG3 complex in cells stimulates autophagy and facilitates the clearance of mutated aggregation-prone proteins, whose accumulation is a hallmark of many neurodegenerative disorders. HSPB8-BAG3 could thus play a protective role in protein aggregation diseases and might be specifically upregulated in response to aggregate-prone protein-mediated toxicity. Here we analysed HSPB8-BAG3 expression levels in post-mortem human brain tissue from patients suffering of the following protein conformation disorders: Alzheimer's disease, Parkinson's disease, Huntington's disease and spinocerebellar ataxia type 3 (SCA3). METHODS: Western blotting and immunohistochemistry techniques were used to analyse HSPB8 and BAG3 expression levels in fibroblasts from SCA3 patients and post-mortem brain tissues, respectively. RESULTS: In all diseases investigated, we observed a strong upregulation of HSPB8 and a moderate upregulation of BAG3 specifically in astrocytes in the cerebral areas affected by neuronal damage and degeneration. Intriguingly, no significant change in the HSPB8-BAG3 expression levels was observed within neurones, irrespective of their localization or of the presence of proteinaceous aggregates. CONCLUSIONS: We propose that the upregulation of HSPB8 and BAG3 may enhance the ability of astrocytes to clear aggregated proteins released from neurones and cellular debris, maintain the local tissue homeostasis and/or participate in the cytoskeletal remodelling that astrocytes undergo during astrogliosis.
    URL, DOI BibTeX

    @article{Seidel2012,
    	abstract = "AIMS: HSPB8 is a small heat shock protein that forms a complex with the co-chaperone BAG3. Overexpression of the HSPB8-BAG3 complex in cells stimulates autophagy and facilitates the clearance of mutated aggregation-prone proteins, whose accumulation is a hallmark of many neurodegenerative disorders. HSPB8-BAG3 could thus play a protective role in protein aggregation diseases and might be specifically upregulated in response to aggregate-prone protein-mediated toxicity. Here we analysed HSPB8-BAG3 expression levels in post-mortem human brain tissue from patients suffering of the following protein conformation disorders: Alzheimer's disease, Parkinson's disease, Huntington's disease and spinocerebellar ataxia type 3 (SCA3). METHODS: Western blotting and immunohistochemistry techniques were used to analyse HSPB8 and BAG3 expression levels in fibroblasts from SCA3 patients and post-mortem brain tissues, respectively. RESULTS: In all diseases investigated, we observed a strong upregulation of HSPB8 and a moderate upregulation of BAG3 specifically in astrocytes in the cerebral areas affected by neuronal damage and degeneration. Intriguingly, no significant change in the HSPB8-BAG3 expression levels was observed within neurones, irrespective of their localization or of the presence of proteinaceous aggregates. CONCLUSIONS: We propose that the upregulation of HSPB8 and BAG3 may enhance the ability of astrocytes to clear aggregated proteins released from neurones and cellular debris, maintain the local tissue homeostasis and/or participate in the cytoskeletal remodelling that astrocytes undergo during astrogliosis.",
    	author = {Seidel, K and Vinet, J and den Dunnen, W F A and Brunt, E R and Meister, M and Boncoraglio, A and Zijlstra, M P and Boddeke, H W G M and R{\"{u}}b, U and Kampinga, H H and Carra, S},
    	doi = "10.1111/j.1365-2990.2011.01198.x",
    	issn = "1365-2990",
    	journal = "Neuropathology and applied neurobiology",
    	keywords = "Adaptor Proteins, Signal Transducing,Adaptor Proteins, Signal Transducing: biosynthesis,Astrocytes,Astrocytes: metabolism,Blotting, Western,Fluorescent Antibody Technique,Heat-Shock Proteins,Heat-Shock Proteins: biosynthesis,Humans,Immunohistochemistry,Neurodegenerative Diseases,Neurodegenerative Diseases: metabolism,Protein-Serine-Threonine Kinases,Protein-Serine-Threonine Kinases: biosynthesis,Up-Regulation",
    	month = "feb",
    	number = 1,
    	pages = "39--53",
    	pmid = 21696420,
    	title = "{The HSPB8-BAG3 chaperone complex is upregulated in astrocytes in the human brain affected by protein aggregation diseases.}",
    	url = "http://www.mendeley.com/catalog/hspb8bag3-chaperone-complex-upregulated-astrocytes-human-brain-affected-protein-aggregation-diseases/",
    	volume = 38,
    	year = 2012
    }
    
  8. Xue-Ying Cui, Nan Wang, Bin-Xia Yang, Wei-Feng Gao, Yong-Min Lin, Xing-Rong Yao and Xiao-Tong Ma.
    HSPB8 is methylated in hematopoietic malignancies and overexpression of HSPB8 exhibits antileukemia effect.. Experimental hematology 40(1):14–21, January 2012.
    Abstract HSPB8 has been shown to be involved in regulation of cell proliferation and apoptosis, and it has also been found to have divergent properties in solid tumors. The purpose of this study was to investigate the expression and function of HSPB8 in hematopoietic malignancies. Expression and induced expression of HSPB8 was evaluated in hematopoietic tumor cell lines and bone marrow samples from patients with leukemia. Methylation status was investigated by methylation-specific polymerase chain reaction. The role of HSPB8 in hematopoietic malignancies was addressed by reintroducing HSPB8 expression into the K562 (leukemia) and Namalwa (lymphoma) cell lines. Expression of HSPB8 was absent in hematopoietic tumor cell lines and primary patient and normal volunteer samples. Promoter DNA methylation of HSPB8 was observed in these cells. HSPB8 expression could be restored after demethylation treatment with 5-aza-2'-deoxycytidine. Overexpression of HSPB8 reduced colony formation of both K562 and Namalwa cell lines, inhibited the cell growth of Namalwa in vitro, and suppressed tumor formation of K562 cells in vivo. The present study demonstrates that HSPB8 is silenced by DNA methylation in hematopoietic malignant and normal cells and its expression can be induced by treatment with 5-aza-2'-deoxycytidine. Overexpression of HSPB8 may have an antitumor activity in chronic myelogenous leukemia and lymphoma.
    URL, DOI BibTeX

    @article{Cui2012,
    	abstract = "HSPB8 has been shown to be involved in regulation of cell proliferation and apoptosis, and it has also been found to have divergent properties in solid tumors. The purpose of this study was to investigate the expression and function of HSPB8 in hematopoietic malignancies. Expression and induced expression of HSPB8 was evaluated in hematopoietic tumor cell lines and bone marrow samples from patients with leukemia. Methylation status was investigated by methylation-specific polymerase chain reaction. The role of HSPB8 in hematopoietic malignancies was addressed by reintroducing HSPB8 expression into the K562 (leukemia) and Namalwa (lymphoma) cell lines. Expression of HSPB8 was absent in hematopoietic tumor cell lines and primary patient and normal volunteer samples. Promoter DNA methylation of HSPB8 was observed in these cells. HSPB8 expression could be restored after demethylation treatment with 5-aza-2'-deoxycytidine. Overexpression of HSPB8 reduced colony formation of both K562 and Namalwa cell lines, inhibited the cell growth of Namalwa in vitro, and suppressed tumor formation of K562 cells in vivo. The present study demonstrates that HSPB8 is silenced by DNA methylation in hematopoietic malignant and normal cells and its expression can be induced by treatment with 5-aza-2'-deoxycytidine. Overexpression of HSPB8 may have an antitumor activity in chronic myelogenous leukemia and lymphoma.",
    	author = "Cui, Xue-Ying and Wang, Nan and Yang, Bin-Xia and Gao, Wei-Feng and Lin, Yong-Min and Yao, Xing-Rong and Ma, Xiao-Tong",
    	doi = "10.1016/j.exphem.2011.09.004",
    	issn = "1873-2399",
    	journal = "Experimental hematology",
    	keywords = "Azacitidine,Azacitidine: analogs {\&} derivatives,Azacitidine: pharmacology,DNA Methylation,DNA Methylation: genetics,Gene Expression Regulation, Neoplastic,Gene Expression Regulation, Neoplastic: drug effec,HL-60 Cells,Heat-Shock Proteins,Heat-Shock Proteins: biosynthesis,Heat-Shock Proteins: deficiency,Heat-Shock Proteins: genetics,Heat-Shock Proteins: metabolism,Hematologic Neoplasms,Hematologic Neoplasms: genetics,Hematologic Neoplasms: metabolism,Hematologic Neoplasms: pathology,Hematologic Neoplasms: therapy,Humans,K562 Cells,Leukemia, Myelogenous, Chronic, BCR-ABL Positive,Leukemia, Myelogenous, Chronic, BCR-ABL Positive:,Lymphoma,Lymphoma: genetics,Lymphoma: metabolism,Lymphoma: pathology,Lymphoma: therapy,Protein-Serine-Threonine Kinases,Protein-Serine-Threonine Kinases: biosynthesis,Protein-Serine-Threonine Kinases: deficiency,Protein-Serine-Threonine Kinases: genetics,Protein-Serine-Threonine Kinases: metabolism,Tumor Cells, Cultured",
    	month = "jan",
    	number = 1,
    	pages = "14--21",
    	pmid = 21914495,
    	title = "{HSPB8 is methylated in hematopoietic malignancies and overexpression of HSPB8 exhibits antileukemia effect.}",
    	url = "http://www.mendeley.com/research/hspb8-methylated-hematopoietic-malignancies-overexpression-hspb8-exhibits-antileukemia-effect/",
    	volume = 40,
    	year = 2012
    }
    
  9. Sheng Chen, Xiaojie Zhang, Lin Song and Weidong Le.
    Autophagy dysregulation in amyotrophic lateral sclerosis.. Brain pathology (Zurich, Switzerland) 22(1):110–6, January 2012.
    Abstract Autophagy is an intracellular lysosomal degradation process, which plays an important role in cell growth and development, and keeping cellular homeostasis in all eukaryotes. Autophagy has multiple physiological functions, including protein degradation, organelle turnover and response to stress. Emerging evidences support the notion that dysregulation of autophagy might be critical for pathogenesis of amyotrophic lateral sclerosis (ALS). The autophagy dysregulation in motor neurons of ALS may occur in different steps of the autophagic process. Recent studies have shown that two ALS associated proteins, TDP-43 and superoxide dismutase 1 (SOD1), are involved in the abnormal autophagy regulation. Furthermore, it is reported that several genetic mutations in ALS disturb the autophagic process in the motor neurons. This review will provide new evidence of autophagy dysregulation as a critical pathogenic process leading to ALS, and will discuss the prospect of future therapeutic targets using autophagic regulation to treat this disease.
    URL, DOI BibTeX

    @article{Chen2012,
    	abstract = "Autophagy is an intracellular lysosomal degradation process, which plays an important role in cell growth and development, and keeping cellular homeostasis in all eukaryotes. Autophagy has multiple physiological functions, including protein degradation, organelle turnover and response to stress. Emerging evidences support the notion that dysregulation of autophagy might be critical for pathogenesis of amyotrophic lateral sclerosis (ALS). The autophagy dysregulation in motor neurons of ALS may occur in different steps of the autophagic process. Recent studies have shown that two ALS associated proteins, TDP-43 and superoxide dismutase 1 (SOD1), are involved in the abnormal autophagy regulation. Furthermore, it is reported that several genetic mutations in ALS disturb the autophagic process in the motor neurons. This review will provide new evidence of autophagy dysregulation as a critical pathogenic process leading to ALS, and will discuss the prospect of future therapeutic targets using autophagic regulation to treat this disease.",
    	author = "Chen, Sheng and Zhang, Xiaojie and Song, Lin and Le, Weidong",
    	doi = "10.1111/j.1750-3639.2011.00546.x",
    	issn = "1750-3639",
    	journal = "Brain pathology (Zurich, Switzerland)",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: genetics,Amyotrophic Lateral Sclerosis: metabolism,Amyotrophic Lateral Sclerosis: pathology,Animals,Autophagy,Autophagy: genetics,Humans,Lysosomes,Lysosomes: metabolism",
    	month = "jan",
    	number = 1,
    	pages = "110--6",
    	pmid = 22150926,
    	title = "{Autophagy dysregulation in amyotrophic lateral sclerosis.}",
    	url = "http://www.mendeley.com/research/autophagy-dysregulation-amyotrophic-lateral-sclerosis/",
    	volume = 22,
    	year = 2012
    }
    
  10. Alice S Kwok, Kanchan Phadwal, Bradley J Turner, Peter L Oliver, Annie Raw, Anna Katharina Simon, Kevin Talbot and Vishwas R Agashe.
    HspB8 mutation causing hereditary distal motor neuropathy impairs lysosomal delivery of autophagosomes.. Journal of neurochemistry 119(6):1155–61, December 2011.
    Abstract HspB8, a small heat-shock protein implicated in autophagy, is mutated in patients with distal hereditary motor neuropathy type II (dHMNII). Autophagy is essential for maintaining protein homeostasis in the central nervous system, but its role has not been investigated in peripheral motor neurons. We used a novel, multispectral-imaging flow cytometry assay to measure autophagy in cells. This assay revealed that over-expression of wild-type HspB8 in motor neuron-like NSC34 cells led to an increased co-localisation of autophagosomes with the lysosomes. By contrast, over-expression of mutant HspB8 resulted in autophagosomes that co-localised with protein aggregates but failed to co-localise with the lysosomes. A similar impairment of autophagy could also be demonstrated in peripheral blood mononuclear cells from two dHMNII patients with the HspB8(K141E) mutation. We conclude that defects in HspB8-mediated autophagy are likely to contribute to dHMNII pathology and their detection in peripheral blood mononuclear cells could be a useful, accessible biomarker for the disease.
    URL, DOI BibTeX

    @article{Kwok2011,
    	abstract = "HspB8, a small heat-shock protein implicated in autophagy, is mutated in patients with distal hereditary motor neuropathy type II (dHMNII). Autophagy is essential for maintaining protein homeostasis in the central nervous system, but its role has not been investigated in peripheral motor neurons. We used a novel, multispectral-imaging flow cytometry assay to measure autophagy in cells. This assay revealed that over-expression of wild-type HspB8 in motor neuron-like NSC34 cells led to an increased co-localisation of autophagosomes with the lysosomes. By contrast, over-expression of mutant HspB8 resulted in autophagosomes that co-localised with protein aggregates but failed to co-localise with the lysosomes. A similar impairment of autophagy could also be demonstrated in peripheral blood mononuclear cells from two dHMNII patients with the HspB8(K141E) mutation. We conclude that defects in HspB8-mediated autophagy are likely to contribute to dHMNII pathology and their detection in peripheral blood mononuclear cells could be a useful, accessible biomarker for the disease.",
    	author = "Kwok, Alice S and Phadwal, Kanchan and Turner, Bradley J and Oliver, Peter L and Raw, Annie and Simon, Anna Katharina and Talbot, Kevin and Agashe, Vishwas R",
    	doi = "10.1111/j.1471-4159.2011.07521.x",
    	isbn = "doi:10.1111/j.1471-4159.2011.07521.x",
    	issn = "1471-4159",
    	journal = "Journal of neurochemistry",
    	keywords = "Analysis of Variance,Autophagy,Autophagy: genetics,Cells, Cultured,Charcot-Marie-Tooth Disease,Charcot-Marie-Tooth Disease: genetics,Charcot-Marie-Tooth Disease: pathology,Flow Cytometry,Heat-Shock Proteins,Heat-Shock Proteins: genetics,Heat-Shock Proteins: metabolism,Humans,Immunoprecipitation,Immunoprecipitation: methods,Leukocytes, Mononuclear,Lysosomes,Lysosomes: physiology,Microtubule-Associated Proteins,Microtubule-Associated Proteins: metabolism,Mutation,Mutation: genetics,Neuroblastoma,Protein Folding,Protein-Serine-Threonine Kinases,Protein-Serine-Threonine Kinases: genetics,Protein-Serine-Threonine Kinases: metabolism,Superoxide Dismutase,Superoxide Dismutase: metabolism,Transfection,Transfection: methods",
    	month = "dec",
    	number = 6,
    	pages = "1155--61",
    	pmid = 21985219,
    	title = "{HspB8 mutation causing hereditary distal motor neuropathy impairs lysosomal delivery of autophagosomes.}",
    	url = "http://www.mendeley.com/research/hspb8-mutation-causing-hereditary-distal-motor-neuropathy-impairs-lysosomal-delivery-autophagosomes/",
    	volume = 119,
    	year = 2011
    }
    
  11. Anton A Shemetov, Alim S Seit-Nebi and Nikolai B Gusev.
    Phosphorylation of human small heat shock protein HspB8 (Hsp22) by ERK1 protein kinase.. Molecular and cellular biochemistry 355(1-2):47–55, September 2011.
    Abstract A number of phosphomimicking mutants (replacement of Ser/Thr residues by Asp) of human small heat shock protein HspB8 were obtained and phosphorylation of the wild type HspB8 and its mutants by ERK1 kinase was analyzed in vitro. Mutation S159D does not affect phosphorylation, whereas mutations S24D and S27D equally moderately inhibited and mutation T87D strongly inhibited phosphorylation of HspB8. The double mutations S24D/T87D and S27D/T87D induced very strong inhibitory effect and the triple mutations S24D/S27D/T87D completely prevented phosphorylation catalyzed by ERK1. Thus, Ser24 and Thr87, found to be phosphorylated in vivo, are among the sites phosphorylated by ERK1 in HspB8 in vitro. Mutations S24D and T87D affect intrinsic tryptophan fluorescence and susceptibility to chymotrypsinolysis of HspB8. Phosphomimicking mutations and phosphorylation promote concentration-dependent association of HspB8 subunits. Mutations S24D and S27D decrease, whereas mutation T87D increases the chaperone-like activity of HspB8. It is concluded that phosphorylation catalyzed by ERK1 might affect the structure and chaperone-like activity of HspB8 and therefore can be important for regulation of interaction of HspB8 with different target proteins.
    URL, DOI BibTeX

    @article{Shemetov2011a,
    	abstract = "A number of phosphomimicking mutants (replacement of Ser/Thr residues by Asp) of human small heat shock protein HspB8 were obtained and phosphorylation of the wild type HspB8 and its mutants by ERK1 kinase was analyzed in vitro. Mutation S159D does not affect phosphorylation, whereas mutations S24D and S27D equally moderately inhibited and mutation T87D strongly inhibited phosphorylation of HspB8. The double mutations S24D/T87D and S27D/T87D induced very strong inhibitory effect and the triple mutations S24D/S27D/T87D completely prevented phosphorylation catalyzed by ERK1. Thus, Ser24 and Thr87, found to be phosphorylated in vivo, are among the sites phosphorylated by ERK1 in HspB8 in vitro. Mutations S24D and T87D affect intrinsic tryptophan fluorescence and susceptibility to chymotrypsinolysis of HspB8. Phosphomimicking mutations and phosphorylation promote concentration-dependent association of HspB8 subunits. Mutations S24D and S27D decrease, whereas mutation T87D increases the chaperone-like activity of HspB8. It is concluded that phosphorylation catalyzed by ERK1 might affect the structure and chaperone-like activity of HspB8 and therefore can be important for regulation of interaction of HspB8 with different target proteins.",
    	author = "Shemetov, Anton A and Seit-Nebi, Alim S and Gusev, Nikolai B",
    	doi = "10.1007/s11010-011-0837-y",
    	issn = "1573-4919",
    	journal = "Molecular and cellular biochemistry",
    	keywords = "Chromatography, Gel,Circular Dichroism,Electrophoresis, Polyacrylamide Gel,Enzyme Assays,Heat-Shock Proteins,Heat-Shock Proteins: chemistry,Humans,Mitogen-Activated Protein Kinase 3,Mitogen-Activated Protein Kinase 3: chemistry,Peptide Fragments,Peptide Fragments: chemistry,Phosphorylation,Protein-Serine-Threonine Kinases,Protein-Serine-Threonine Kinases: chemistry,Spectrometry, Fluorescence",
    	month = "sep",
    	number = "1-2",
    	pages = "47--55",
    	pmid = 21526341,
    	title = "{Phosphorylation of human small heat shock protein HspB8 (Hsp22) by ERK1 protein kinase.}",
    	url = "http://www.mendeley.com/research/phosphorylation-human-small-heat-shock-protein-hspb8-hsp22-erk1-protein-kinase/",
    	volume = 355,
    	year = 2011
    }
    
  12. Anton A Shemetov and Nikolai B Gusev.
    Biochemical characterization of small heat shock protein HspB8 (Hsp22)-Bag3 interaction.. Archives of biochemistry and biophysics 513(1):1–9, September 2011.
    Abstract Interaction of human Bag3 with small heat shock proteins HspB6, HspB8 and its K141E mutant was analyzed by different biochemical methods. The data of size-exclusion chromatography indicate that the wild type HspB8 forms tight complexes with Bag3. K141E mutant of HspB8 and especially HspB6 weaker interact with Bag3. The data of chemical crosslinking and analytical ultracentrifugation indicate that in vitro the stoichiometry of complexes formed by HspB8 and Bag3 is variable and is dependent on concentration of protein partners. Interaction of Bag3 and HspB8 is accompanied by increase of thermal stability measured by intrinsic tryptophan fluorescence and increased resistance to limited chymotrypsinolysis. The data of size-exclusion chromatography, analytical ultracentrifugation and limited proteolysis indicate that Bag3 belongs to the group of intrinsically disordered proteins. It is supposed that having unordered structure Bag3 might weakly interact with different small heat shock proteins which recognize unfolded proteins and this interaction is especially strong with intrinsically disordered HspB8. The complexes formed by Bag3 and HspB8 might have variable stoichiometry and can participate in different processes including clearing of the cell from improperly folded proteins.
    URL, DOI BibTeX

    @article{Shemetov2011,
    	abstract = "Interaction of human Bag3 with small heat shock proteins HspB6, HspB8 and its K141E mutant was analyzed by different biochemical methods. The data of size-exclusion chromatography indicate that the wild type HspB8 forms tight complexes with Bag3. K141E mutant of HspB8 and especially HspB6 weaker interact with Bag3. The data of chemical crosslinking and analytical ultracentrifugation indicate that in vitro the stoichiometry of complexes formed by HspB8 and Bag3 is variable and is dependent on concentration of protein partners. Interaction of Bag3 and HspB8 is accompanied by increase of thermal stability measured by intrinsic tryptophan fluorescence and increased resistance to limited chymotrypsinolysis. The data of size-exclusion chromatography, analytical ultracentrifugation and limited proteolysis indicate that Bag3 belongs to the group of intrinsically disordered proteins. It is supposed that having unordered structure Bag3 might weakly interact with different small heat shock proteins which recognize unfolded proteins and this interaction is especially strong with intrinsically disordered HspB8. The complexes formed by Bag3 and HspB8 might have variable stoichiometry and can participate in different processes including clearing of the cell from improperly folded proteins.",
    	author = "Shemetov, Anton A and Gusev, Nikolai B",
    	doi = "10.1016/j.abb.2011.06.014",
    	issn = "1096-0384",
    	journal = "Archives of biochemistry and biophysics",
    	keywords = "Adaptor Proteins, Signal Transducing,Adaptor Proteins, Signal Transducing: chemistry,Adaptor Proteins, Signal Transducing: genetics,Adaptor Proteins, Signal Transducing: metabolism,Amino Acid Substitution,Heat-Shock Proteins,Heat-Shock Proteins: chemistry,Heat-Shock Proteins: genetics,Heat-Shock Proteins: metabolism,Humans,Multiprotein Complexes,Multiprotein Complexes: chemistry,Multiprotein Complexes: genetics,Multiprotein Complexes: metabolism,Mutation, Missense,Protein Folding,Protein Stability,Protein-Serine-Threonine Kinases,Protein-Serine-Threonine Kinases: chemistry,Protein-Serine-Threonine Kinases: genetics,Protein-Serine-Threonine Kinases: metabolism,Recombinant Proteins,Recombinant Proteins: chemistry,Recombinant Proteins: genetics,Recombinant Proteins: metabolism",
    	month = "sep",
    	number = 1,
    	pages = "1--9",
    	pmid = 21767525,
    	title = "{Biochemical characterization of small heat shock protein HspB8 (Hsp22)-Bag3 interaction.}",
    	url = "http://www.mendeley.com/catalog/biochemical-characterization-small-heat-shock-protein-hspb8-hsp22bag3-interaction/",
    	volume = 513,
    	year = 2011
    }
    
  13. Valeria Crippa, Serena Carra, Paola Rusmini, Daniela Sau, Elena Bolzoni, Caterina Bendotti, Silvia De Biasi and Angelo Poletti.
    A role of small heat shock protein B8 (HspB8) in the autophagic removal of misfolded proteins responsible for neurodegenerative diseases.. Autophagy 6(7):958–60, October 2010.
    Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of upper and lower motor neurons. As with other age-dependent neurodegenerative disorders, ALS is linked to the presence of misfolded proteins that may perturb several intracellular mechanisms and trigger neurotoxicity. Misfolded proteins aggregate intracellularly generating insoluble inclusions that are a key neuropathological hallmark of ALS. Proteins involved in the intracellular degradative systems, signaling pathways and the human TAR DNA-binding protein TDP-43 are major components of these inclusions. While their role and cytotoxicity are still largely debated, aggregates represent a powerful marker to follow protein misfolding in the neurodegenerative processes. Using in vitro and in vivo models of mutant SOD1 associated familial ALS (fALS), we and other groups demonstrated that protein misfolding perturbs one of the major intracellular degradative pathways, the ubiquitin proteasome system, giving rise to a vicious cycle that leads to the further deposit of insoluble proteins and finally to the formation of inclusions. The aberrant response to mutated SOD1 thus leads to the activation of the cascade of events ultimately responsible for cell death. Hence, our idea is that, by assisting protein folding, we might reduce protein aggregation, restore a fully functional proteasome activity and/or other cascades of events triggered by the mutant proteins responsible for motor neuron death in ALS. This could be obtained by stimulating mutant protein turnover, using an alternative degradative pathway that could clear mutant SOD1, namely autophagy.
    URL, DOI BibTeX

    @article{Crippa2010,
    	abstract = "Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of upper and lower motor neurons. As with other age-dependent neurodegenerative disorders, ALS is linked to the presence of misfolded proteins that may perturb several intracellular mechanisms and trigger neurotoxicity. Misfolded proteins aggregate intracellularly generating insoluble inclusions that are a key neuropathological hallmark of ALS. Proteins involved in the intracellular degradative systems, signaling pathways and the human TAR DNA-binding protein TDP-43 are major components of these inclusions. While their role and cytotoxicity are still largely debated, aggregates represent a powerful marker to follow protein misfolding in the neurodegenerative processes. Using in vitro and in vivo models of mutant SOD1 associated familial ALS (fALS), we and other groups demonstrated that protein misfolding perturbs one of the major intracellular degradative pathways, the ubiquitin proteasome system, giving rise to a vicious cycle that leads to the further deposit of insoluble proteins and finally to the formation of inclusions. The aberrant response to mutated SOD1 thus leads to the activation of the cascade of events ultimately responsible for cell death. Hence, our idea is that, by assisting protein folding, we might reduce protein aggregation, restore a fully functional proteasome activity and/or other cascades of events triggered by the mutant proteins responsible for motor neuron death in ALS. This could be obtained by stimulating mutant protein turnover, using an alternative degradative pathway that could clear mutant SOD1, namely autophagy.",
    	author = "Crippa, Valeria and Carra, Serena and Rusmini, Paola and Sau, Daniela and Bolzoni, Elena and Bendotti, Caterina and {De Biasi}, Silvia and Poletti, Angelo",
    	doi = "10.4161/auto.6.7.13042",
    	issn = "1554-8635",
    	journal = "Autophagy",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: genetics,Amyotrophic Lateral Sclerosis: metabolism,Amyotrophic Lateral Sclerosis: pathology,Animals,Autophagy,Autophagy: physiology,Heat-Shock Proteins,Heat-Shock Proteins: metabolism,Humans,Inclusion Bodies,Inclusion Bodies: metabolism,Motor Neurons,Motor Neurons: metabolism,Motor Neurons: pathology,Neurodegenerative Diseases,Neurodegenerative Diseases: genetics,Neurodegenerative Diseases: metabolism,Neurodegenerative Diseases: pathology,Proteasome Endopeptidase Complex,Proteasome Endopeptidase Complex: metabolism,Protein Conformation,Protein Folding,Protein-Serine-Threonine Kinases,Protein-Serine-Threonine Kinases: metabolism,Superoxide Dismutase,Superoxide Dismutase: chemistry,Superoxide Dismutase: genetics,Superoxide Dismutase: metabolism",
    	month = "oct",
    	number = 7,
    	pages = "958--60",
    	pmid = 20699640,
    	title = "{A role of small heat shock protein B8 (HspB8) in the autophagic removal of misfolded proteins responsible for neurodegenerative diseases.}",
    	url = "http://www.mendeley.com/catalog/role-small-heat-shock-protein-b8-hspb8-autophagic-removal-misfolded-proteins-responsible-neurodegene/",
    	volume = 6,
    	year = 2010
    }
    
  14. Valeria Crippa, Daniela Sau, Paola Rusmini, Alessandra Boncoraglio, Elisa Onesto, Elena Bolzoni, Mariarita Galbiati, Elena Fontana, Marianna Marino, Serena Carra, Caterina Bendotti, Silvia De Biasi and Angelo Poletti.
    The small heat shock protein B8 (HspB8) promotes autophagic removal of misfolded proteins involved in amyotrophic lateral sclerosis (ALS).. Human molecular genetics 19(17):3440–56, September 2010.
    Abstract Several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), are characterized by the presence of misfolded proteins, thought to trigger neurotoxicity. Some familial forms of ALS (fALS), clinically indistinguishable from sporadic ALS (sALS), are linked to superoxide dismutase 1 (SOD1) gene mutations. It has been shown that the mutant SOD1 misfolds, forms insoluble aggregates and impairs the proteasome. Using transgenic G93A-SOD1 mice, we found that spinal cord motor neurons, accumulating mutant SOD1 also over-express the small heat shock protein HspB8. Using motor neuronal fALS models, we demonstrated that HspB8 decreases aggregation and increases mutant SOD1 solubility and clearance, without affecting wild-type SOD1 turnover. Notably, HspB8 acts on mutant SOD1 even when the proteasome activity is specifically blocked. The pharmacological blockage of autophagy resulted in a dramatic increase of mutant SOD1 aggregates. Immunoprecipitation studies, performed during autophagic flux blockage, demonstrated that mutant SOD1 interacts with the HspB8/Bag3/Hsc70/CHIP multiheteromeric complex, known to selectively activate autophagic removal of misfolded proteins. Thus, HspB8 increases mutant SOD1 clearance via autophagy. Autophagy activation was also observed in lumbar spinal cord of transgenic G93A-SOD1 mice since several autophago-lysosomal structures were present in affected surviving motor neurons. Finally, we extended our observation to a different ALS model and demonstrated that HspB8 exerts similar effects on a truncated version of TDP-43, another protein involved both in fALS and in sALS. Overall, these results indicate that the pharmacological modulation of HspB8 expression in motor neurons may have important implications to unravel the molecular mechanisms involved both in fALS and in sALS.
    URL, DOI BibTeX

    @article{Crippa2010a,
    	abstract = "Several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), are characterized by the presence of misfolded proteins, thought to trigger neurotoxicity. Some familial forms of ALS (fALS), clinically indistinguishable from sporadic ALS (sALS), are linked to superoxide dismutase 1 (SOD1) gene mutations. It has been shown that the mutant SOD1 misfolds, forms insoluble aggregates and impairs the proteasome. Using transgenic G93A-SOD1 mice, we found that spinal cord motor neurons, accumulating mutant SOD1 also over-express the small heat shock protein HspB8. Using motor neuronal fALS models, we demonstrated that HspB8 decreases aggregation and increases mutant SOD1 solubility and clearance, without affecting wild-type SOD1 turnover. Notably, HspB8 acts on mutant SOD1 even when the proteasome activity is specifically blocked. The pharmacological blockage of autophagy resulted in a dramatic increase of mutant SOD1 aggregates. Immunoprecipitation studies, performed during autophagic flux blockage, demonstrated that mutant SOD1 interacts with the HspB8/Bag3/Hsc70/CHIP multiheteromeric complex, known to selectively activate autophagic removal of misfolded proteins. Thus, HspB8 increases mutant SOD1 clearance via autophagy. Autophagy activation was also observed in lumbar spinal cord of transgenic G93A-SOD1 mice since several autophago-lysosomal structures were present in affected surviving motor neurons. Finally, we extended our observation to a different ALS model and demonstrated that HspB8 exerts similar effects on a truncated version of TDP-43, another protein involved both in fALS and in sALS. Overall, these results indicate that the pharmacological modulation of HspB8 expression in motor neurons may have important implications to unravel the molecular mechanisms involved both in fALS and in sALS.",
    	author = "Crippa, Valeria and Sau, Daniela and Rusmini, Paola and Boncoraglio, Alessandra and Onesto, Elisa and Bolzoni, Elena and Galbiati, Mariarita and Fontana, Elena and Marino, Marianna and Carra, Serena and Bendotti, Caterina and {De Biasi}, Silvia and Poletti, Angelo",
    	doi = "10.1093/hmg/ddq257",
    	issn = "1460-2083",
    	journal = "Human molecular genetics",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: genetics,Amyotrophic Lateral Sclerosis: metabolism,Amyotrophic Lateral Sclerosis: physiopathology,Animals,Autophagy,Cell Line,DNA-Binding Proteins,DNA-Binding Proteins: genetics,DNA-Binding Proteins: metabolism,Female,HSP20 Heat-Shock Proteins,HSP20 Heat-Shock Proteins: genetics,HSP20 Heat-Shock Proteins: metabolism,Heat-Shock Proteins,Heat-Shock Proteins: genetics,Heat-Shock Proteins: metabolism,Humans,Male,Mice,Mice, Inbred C57BL,Mice, Transgenic,Motor Neurons,Motor Neurons: metabolism,Muscle Proteins,Muscle Proteins: genetics,Muscle Proteins: metabolism,Protein Folding,Protein-Serine-Threonine Kinases,Protein-Serine-Threonine Kinases: genetics,Protein-Serine-Threonine Kinases: metabolism,Superoxide Dismutase,Superoxide Dismutase: chemistry,Superoxide Dismutase: genetics,Superoxide Dismutase: metabolism",
    	month = "sep",
    	number = 17,
    	pages = "3440--56",
    	pmid = 20570967,
    	title = "{The small heat shock protein B8 (HspB8) promotes autophagic removal of misfolded proteins involved in amyotrophic lateral sclerosis (ALS).}",
    	url = "http://www.mendeley.com/catalog/small-heat-shock-protein-b8-hspb8-promotes-autophagic-removal-misfolded-proteins-involved-amyotrophi/",
    	volume = 19,
    	year = 2010
    }
    
  15. S Carra, A Boncoraglio, B Kanon, J F Brunsting, M Minoia, A Rana, M J Vos, K Seidel, O C M Sibon and H H Kampinga.
    Identification of the Drosophila Ortholog of HSPB8: IMPLICATION OF HSPB8 LOSS OF FUNCTION IN PROTEIN FOLDING DISEASES. Journal of Biological Chemistry 285(48):37811–37822, September 2010.
    URL, DOI BibTeX

    @article{Carra2010,
    	author = "Carra, S. and Boncoraglio, A. and Kanon, B. and Brunsting, J. F. and Minoia, M. and Rana, A. and Vos, M. J. and Seidel, K. and Sibon, O. C. M. and Kampinga, H. H.",
    	doi = "10.1074/jbc.M110.127498",
    	issn = "0021-9258",
    	journal = "Journal of Biological Chemistry",
    	month = "sep",
    	number = 48,
    	pages = "37811--37822",
    	title = "{Identification of the Drosophila Ortholog of HSPB8: IMPLICATION OF HSPB8 LOSS OF FUNCTION IN PROTEIN FOLDING DISEASES}",
    	url = "http://www.mendeley.com/catalog/identification-drosophila-ortholog-hspb8-implication-hspb8-loss-function-protein-folding-diseases/",
    	volume = 285,
    	year = 2010
    }
    
  16. J Irobi, L Almeida-Souza, B Asselbergh, V De Winter, S Goethals, I Dierick, J Krishnan, J -P Timmermans, W Robberecht, P De Jonghe, L Van Den Bosch, S Janssens and V Timmerman.
    Mutant HSPB8 causes motor neuron-specific neurite degeneration. Human Molecular Genetics 19(16):3254–3265, June 2010.
    URL, DOI BibTeX

    @article{Irobi2010,
    	author = "Irobi, J. and Almeida-Souza, L. and Asselbergh, B. and {De Winter}, V. and Goethals, S. and Dierick, I. and Krishnan, J. and Timmermans, J.-P. and Robberecht, W. and {De Jonghe}, P. and {Van Den Bosch}, L. and Janssens, S. and Timmerman, V.",
    	doi = "10.1093/hmg/ddq234",
    	issn = "0964-6906",
    	journal = "Human Molecular Genetics",
    	month = "jun",
    	number = 16,
    	pages = "3254--3265",
    	title = "{Mutant HSPB8 causes motor neuron-specific neurite degeneration}",
    	url = "http://www.mendeley.com/catalog/mutant-hspb8-causes-motor-neuronspecific-neurite-degeneration/",
    	volume = 19,
    	year = 2010
    }
    
  17. Margit Fuchs, Dominic J Poirier, Samuel J Seguin, Herman Lambert, Serena Carra, Steve J Charette and Jacques Landry.
    Identification of the key structural motifs involved in HspB8/HspB6-Bag3 interaction.. The Biochemical journal 425(1):245–55, January 2010.
    Abstract The molecular chaperone HspB8 [Hsp (heat-shock protein) B8] is member of the B-group of Hsps. These proteins bind to unfolded or misfolded proteins and protect them from aggregation. HspB8 has been reported to form a stable molecular complex with the chaperone cohort protein Bag3 (Bcl-2-associated athanogene 3). In the present study we identify the binding regions in HspB8 and Bag3 crucial for their interaction. We present evidence that HspB8 binds to Bag3 through the hydrophobic groove formed by its strands beta4 and beta8, a region previously known to be responsible for the formation and stability of higher-order oligomers of many sHsps (small Hsps). Moreover, we demonstrate that two conserved IPV (Ile-Pro-Val) motifs in Bag3 mediate its binding to HspB8 and that deletion of these motifs suppresses HspB8 chaperone activity towards mutant Htt43Q (huntingtin exon 1 fragment with 43 CAG repeats). In addition, we show that Bag3 can bind to the molecular chaperone HspB6. The interaction between HspB6 and Bag3 requires the same regions that are involved in the HspB8-Bag3 association and HspB6-Bag3 promotes clearance of aggregated Htt43Q. Our findings suggest that the co-chaperone Bag3 might prevent the accumulation of denatured proteins by regulating sHsp activity and by targeting their substrate proteins for degradation. Interestingly, a mutation in one of Bag3 IPV motifs has recently been associated with the development of severe dominant childhood muscular dystrophy, suggesting a possible important physiological role for HspB-Bag3 complexes in this disease.
    URL, DOI BibTeX

    @article{Fuchs2010,
    	abstract = "The molecular chaperone HspB8 [Hsp (heat-shock protein) B8] is member of the B-group of Hsps. These proteins bind to unfolded or misfolded proteins and protect them from aggregation. HspB8 has been reported to form a stable molecular complex with the chaperone cohort protein Bag3 (Bcl-2-associated athanogene 3). In the present study we identify the binding regions in HspB8 and Bag3 crucial for their interaction. We present evidence that HspB8 binds to Bag3 through the hydrophobic groove formed by its strands beta4 and beta8, a region previously known to be responsible for the formation and stability of higher-order oligomers of many sHsps (small Hsps). Moreover, we demonstrate that two conserved IPV (Ile-Pro-Val) motifs in Bag3 mediate its binding to HspB8 and that deletion of these motifs suppresses HspB8 chaperone activity towards mutant Htt43Q (huntingtin exon 1 fragment with 43 CAG repeats). In addition, we show that Bag3 can bind to the molecular chaperone HspB6. The interaction between HspB6 and Bag3 requires the same regions that are involved in the HspB8-Bag3 association and HspB6-Bag3 promotes clearance of aggregated Htt43Q. Our findings suggest that the co-chaperone Bag3 might prevent the accumulation of denatured proteins by regulating sHsp activity and by targeting their substrate proteins for degradation. Interestingly, a mutation in one of Bag3 IPV motifs has recently been associated with the development of severe dominant childhood muscular dystrophy, suggesting a possible important physiological role for HspB-Bag3 complexes in this disease.",
    	author = "Fuchs, Margit and Poirier, Dominic J and Seguin, Samuel J and Lambert, Herman and Carra, Serena and Charette, Steve J and Landry, Jacques",
    	doi = "10.1042/BJ20090907",
    	issn = "1470-8728",
    	journal = "The Biochemical journal",
    	keywords = "Adaptor Proteins, Signal Transducing,Adaptor Proteins, Signal Transducing: chemistry,Adaptor Proteins, Signal Transducing: genetics,Adaptor Proteins, Signal Transducing: metabolism,Amino Acid Motifs,Amino Acid Sequence,Binding Sites,Binding Sites: genetics,Blotting, Western,Cell Line,HSP20 Heat-Shock Proteins,HSP20 Heat-Shock Proteins: chemistry,HSP20 Heat-Shock Proteins: genetics,HSP20 Heat-Shock Proteins: metabolism,Heat-Shock Proteins,Heat-Shock Proteins: chemistry,Heat-Shock Proteins: genetics,Heat-Shock Proteins: metabolism,Humans,Hydrophobic and Hydrophilic Interactions,Immunoprecipitation,Molecular Chaperones,Molecular Chaperones: genetics,Molecular Chaperones: metabolism,Molecular Sequence Data,Mutation,Nerve Tissue Proteins,Nerve Tissue Proteins: genetics,Nerve Tissue Proteins: metabolism,Nuclear Proteins,Nuclear Proteins: genetics,Nuclear Proteins: metabolism,Protein Binding,Protein-Serine-Threonine Kinases,Protein-Serine-Threonine Kinases: chemistry,Protein-Serine-Threonine Kinases: genetics,Protein-Serine-Threonine Kinases: metabolism,Sequence Homology, Amino Acid,Transfection,Trinucleotide Repeats,Trinucleotide Repeats: genetics",
    	month = "jan",
    	number = 1,
    	pages = "245--55",
    	pmid = 19845507,
    	title = "{Identification of the key structural motifs involved in HspB8/HspB6-Bag3 interaction.}",
    	url = "http://www.mendeley.com/research/identification-key-structural-motifs-involved-hspb8hspb6bag3-interaction/",
    	volume = 425,
    	year = 2010
    }
    
  18. Serena Carra.
    The stress-inducible HspB8-Bag3 complex induces the eIF2$\alpha$ kinase pathway: Implications for protein quality control and viral factory degradation?. Autophagy 5(3):428–430, April 2009.
    URL, DOI BibTeX

    @article{Carra2009a,
    	author = "Carra, Serena",
    	doi = "10.4161/auto.5.3.7894",
    	issn = "1554-8627",
    	journal = "Autophagy",
    	month = "apr",
    	number = 3,
    	pages = "428--430",
    	title = "{The stress-inducible HspB8-Bag3 complex induces the eIF2$\alpha$ kinase pathway: Implications for protein quality control and viral factory degradation?}",
    	url = "http://www.mendeley.com/research/stressinducible-hspb8bag3-complex-induces-eif2alpha-kinase-pathway-implications-protein-quality-cont/",
    	volume = 5,
    	year = 2009
    }
    
  19. Serena Carra, Jeanette F Brunsting, Herman Lambert, Jacques Landry and Harm H Kampinga.
    {HspB8 participates in protein quality control by a non-chaperone-like mechanism that requires eIF2{alpha} phosphorylation.}. The Journal of biological chemistry 284(9):5523–32, March 2009.
    Abstract Aggregation of mutated proteins is a hallmark of many neurodegenerative disorders, including Huntington disease. We previously reported that overexpression of the HspB8.Bag3 chaperone complex suppresses mutated huntingtin aggregation via autophagy. Classically, HspB proteins are thought to act as ATP-independent molecular chaperones that can bind unfolded proteins and facilitate their processing via the help of ATP-dependent chaperones such as the Hsp70 machine, in which Bag3 may act as a molecular link between HspB, Hsp70, and the ubiquitin ligases. However, here we show that HspB8 and Bag3 act in a non-canonical manner unrelated to the classical chaperone model. Rather, HspB8 and Bag3 induce the phosphorylation of the alpha-subunit of the translation initiator factor eIF2, which in turn causes a translational shut-down and stimulates autophagy. This function of HspB8.Bag3 does not require Hsp70 and also targets fully folded substrates. HspB8.Bag3 activity was independent of the endoplasmic reticulum (ER) stress kinase PERK, demonstrating that its action is unrelated to ER stress and suggesting that it activates stress-mediated translational arrest and autophagy through a novel pathway.
    URL, DOI BibTeX

    @article{Carra2009,
    	abstract = "Aggregation of mutated proteins is a hallmark of many neurodegenerative disorders, including Huntington disease. We previously reported that overexpression of the HspB8.Bag3 chaperone complex suppresses mutated huntingtin aggregation via autophagy. Classically, HspB proteins are thought to act as ATP-independent molecular chaperones that can bind unfolded proteins and facilitate their processing via the help of ATP-dependent chaperones such as the Hsp70 machine, in which Bag3 may act as a molecular link between HspB, Hsp70, and the ubiquitin ligases. However, here we show that HspB8 and Bag3 act in a non-canonical manner unrelated to the classical chaperone model. Rather, HspB8 and Bag3 induce the phosphorylation of the alpha-subunit of the translation initiator factor eIF2, which in turn causes a translational shut-down and stimulates autophagy. This function of HspB8.Bag3 does not require Hsp70 and also targets fully folded substrates. HspB8.Bag3 activity was independent of the endoplasmic reticulum (ER) stress kinase PERK, demonstrating that its action is unrelated to ER stress and suggesting that it activates stress-mediated translational arrest and autophagy through a novel pathway.",
    	author = "Carra, Serena and Brunsting, Jeanette F and Lambert, Herman and Landry, Jacques and Kampinga, Harm H",
    	doi = "10.1074/jbc.M807440200",
    	issn = "0021-9258",
    	journal = "The Journal of biological chemistry",
    	keywords = "Adaptor Proteins, Signal Transducing,Adaptor Proteins, Signal Transducing: genetics,Adaptor Proteins, Signal Transducing: metabolism,Animals,Autophagy,Cells, Cultured,Embryo, Mammalian,Embryo, Mammalian: cytology,Embryo, Mammalian: metabolism,Eukaryotic Initiation Factor-2,Eukaryotic Initiation Factor-2: genetics,Eukaryotic Initiation Factor-2: metabolism,Fibroblasts,Fibroblasts: cytology,Fibroblasts: metabolism,Heat-Shock Proteins,Heat-Shock Proteins: genetics,Heat-Shock Proteins: metabolism,Humans,Mice,Mice, Knockout,Microtubule-Associated Proteins,Microtubule-Associated Proteins: physiology,Molecular Chaperones,Nerve Tissue Proteins,Nerve Tissue Proteins: genetics,Nerve Tissue Proteins: metabolism,Nuclear Proteins,Nuclear Proteins: genetics,Nuclear Proteins: metabolism,Phosphorylation,Protein Biosynthesis,Protein-Serine-Threonine Kinases,Protein-Serine-Threonine Kinases: genetics,Protein-Serine-Threonine Kinases: metabolism,Protein-Serine-Threonine Kinases: physiology,RNA Stability,Recombinant Proteins,Recombinant Proteins: genetics,Recombinant Proteins: isolation {\&} purification,Recombinant Proteins: metabolism,Trinucleotide Repeats,eIF-2 Kinase,eIF-2 Kinase: physiology",
    	month = "mar",
    	number = 9,
    	pages = "5523--32",
    	pmid = 19114712,
    	title = "{HspB8 participates in protein quality control by a non-chaperone-like mechanism that requires eIF2{\{}alpha{\}} phosphorylation.}",
    	url = "http://www.mendeley.com/research/hspb8-participates-protein-quality-control-nonchaperonelike-mechanism-requires-eif2alpha-phosphoryla/",
    	volume = 284,
    	year = 2009
    }
    
  20. Atsushi Sanbe, Takuya Daicho, Reiko Mizutani, Toshiya Endo, Noriko Miyauchi, Junji Yamauchi, Kouichi Tanonaka, Charles Glabe and Akito Tanoue.
    Protective effect of geranylgeranylacetone via enhancement of HSPB8 induction in desmin-related cardiomyopathy.. PloS one 4(4):e5351, January 2009.
    Abstract BACKGROUND: An arg120gly (R120G) missense mutation in HSPB5 (alpha-beta-crystallin ), which belongs to the small heat shock protein (HSP) family, causes desmin-related cardiomyopathy (DRM), a muscle disease that is characterized by the formation of inclusion bodies, which can contain pre-amyloid oligomer intermediates (amyloid oligomer). While we have shown that small HSPs can directly interrupt amyloid oligomer formation, the in vivo protective effects of the small HSPs on the development of DRM is still uncertain. METHODOLOGY/PRINCIPAL FINDINGS: In order to extend the previous in vitro findings to in vivo, we used geranylgeranylacetone (GGA), a potent HSP inducer. Oral administration of GGA resulted not only in up-regulation of the expression level of HSPB8 and HSPB1 in the heart of HSPB5 R120G transgenic (R120G TG) mice, but also reduced amyloid oligomer levels and aggregates. Furthermore, R120G TG mice treated with GGA exhibited decreased heart size and less interstitial fibrosis, as well as improved cardiac function and survival compared to untreated R120G TG mice. To address possible mechanism(s) for these beneficial effects, cardiac-specific transgenic mice expressing HSPB8 were generated. Overexpression of HSPB8 led to a reduction in amyloid oligomer and aggregate formation, resulting in improved cardiac function and survival. Treatment with GGA as well as the overexpression of HSPB8 also inhibited cytochrome c release from mitochondria, activation of caspase-3 and TUNEL-positive cardiomyocyte death in the R120G TG mice. CONCLUSIONS/SIGNIFICANCE: Expression of small HSPs such as HSPB8 and HSPB1 by GGA may be a new therapeutic strategy for patients with DRM.
    URL, DOI BibTeX

    @article{Sanbe2009,
    	abstract = "BACKGROUND: An arg120gly (R120G) missense mutation in HSPB5 (alpha-beta-crystallin ), which belongs to the small heat shock protein (HSP) family, causes desmin-related cardiomyopathy (DRM), a muscle disease that is characterized by the formation of inclusion bodies, which can contain pre-amyloid oligomer intermediates (amyloid oligomer). While we have shown that small HSPs can directly interrupt amyloid oligomer formation, the in vivo protective effects of the small HSPs on the development of DRM is still uncertain. METHODOLOGY/PRINCIPAL FINDINGS: In order to extend the previous in vitro findings to in vivo, we used geranylgeranylacetone (GGA), a potent HSP inducer. Oral administration of GGA resulted not only in up-regulation of the expression level of HSPB8 and HSPB1 in the heart of HSPB5 R120G transgenic (R120G TG) mice, but also reduced amyloid oligomer levels and aggregates. Furthermore, R120G TG mice treated with GGA exhibited decreased heart size and less interstitial fibrosis, as well as improved cardiac function and survival compared to untreated R120G TG mice. To address possible mechanism(s) for these beneficial effects, cardiac-specific transgenic mice expressing HSPB8 were generated. Overexpression of HSPB8 led to a reduction in amyloid oligomer and aggregate formation, resulting in improved cardiac function and survival. Treatment with GGA as well as the overexpression of HSPB8 also inhibited cytochrome c release from mitochondria, activation of caspase-3 and TUNEL-positive cardiomyocyte death in the R120G TG mice. CONCLUSIONS/SIGNIFICANCE: Expression of small HSPs such as HSPB8 and HSPB1 by GGA may be a new therapeutic strategy for patients with DRM.",
    	author = "Sanbe, Atsushi and Daicho, Takuya and Mizutani, Reiko and Endo, Toshiya and Miyauchi, Noriko and Yamauchi, Junji and Tanonaka, Kouichi and Glabe, Charles and Tanoue, Akito",
    	doi = "10.1371/journal.pone.0005351",
    	file = ":C$\backslash$:/Users/Riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Sanbe et al. - 2009 - Protective effect of geranylgeranylacetone via enhancement of HSPB8 induction in desmin-related cardiomyopathy.pdf:pdf",
    	issn = "1932-6203",
    	journal = "PloS one",
    	keywords = "Amyloid,Amyloid: metabolism,Animals,Apoptosis,Apoptosis: drug effects,Cardiomyopathies,Cardiomyopathies: genetics,Cardiomyopathies: metabolism,Cardiomyopathies: prevention {\&} control,Caspase 3,Caspase 3: metabolism,Cytochromes c,Cytochromes c: metabolism,Desmin,Desmin: metabolism,Diterpenes,Diterpenes: pharmacology,HSP20 Heat-Shock Proteins,HSP20 Heat-Shock Proteins: biosynthesis,HSP20 Heat-Shock Proteins: genetics,Heat-Shock Proteins,Heat-Shock Proteins: biosynthesis,Heat-Shock Proteins: genetics,Male,Mice,Mice, Inbred C57BL,Mice, Transgenic,Muscle Proteins,Muscle Proteins: biosynthesis,Muscle Proteins: genetics,Mutation, Missense,Myocardium,Myocardium: metabolism,Myocardium: pathology,Myocytes, Cardiac,Myocytes, Cardiac: drug effects,Myocytes, Cardiac: metabolism,Neoplasm Proteins,Neoplasm Proteins: biosynthesis,Neoplasm Proteins: genetics,Rats,Up-Regulation,Up-Regulation: drug effects",
    	month = "jan",
    	number = 4,
    	pages = "e5351",
    	pmid = 19399179,
    	title = "{Protective effect of geranylgeranylacetone via enhancement of HSPB8 induction in desmin-related cardiomyopathy.}",
    	url = "http://www.mendeley.com/catalog/protective-effect-geranylgeranylacetone-via-enhancement-hspb8-induction-desminrelated-cardiomyopathy/",
    	volume = 4,
    	year = 2009
    }
    
  21. Serena Carra, Samuel J Seguin and Jacques Landry.
    HspB8 and Bag3: a new chaperone complex targeting misfolded proteins to macroautophagy.. Autophagy 4(2):237–239, 2008.
    URL BibTeX

    @article{Carra2008a,
    	author = "Carra, Serena and Seguin, Samuel J and Landry, Jacques",
    	issn = "1554-8635",
    	journal = "Autophagy",
    	number = 2,
    	pages = "237--239",
    	title = "{HspB8 and Bag3: a new chaperone complex targeting misfolded proteins to macroautophagy.}",
    	url = "http://www.mendeley.com/research/hspb8-bag3-new-chaperone-complex-targeting-misfolded-proteins-macroautophagy/",
    	volume = 4,
    	year = 2008
    }
    
  22. Serena Carra, Samuel J Seguin, Herman Lambert and Jacques Landry.
    HspB8 chaperone activity toward poly(Q)-containing proteins depends on its association with Bag3, a stimulator of macroautophagy.. The Journal of biological chemistry 283(3):1437–44, January 2008.
    Abstract Mutations in HspB8, a member of the B group of heat shock proteins (Hsp), have been associated with human neuromuscular disorders. However, the exact function of HspB8 is not yet clear. We previously demonstrated that overexpression of HspB8 in cultured cells prevents the accumulation of aggregation-prone proteins such as the polyglutamine protein Htt43Q. Here we report that HspB8 forms a stable complex with Bag3 in cells and that the formation of this complex is essential for the activity of HspB8. Bag3 overexpression resulted in the accelerated degradation of Htt43Q, whereas Bag3 knockdown prevented HspB8-induced Htt43Q degradation. Additionally, depleting Bag3 caused a reduction in the endogenous levels of LC3-II, a key molecule involved in macroautophagy, whereas overexpressing Bag3 or HspB8 stimulated the formation LC3-II. These results suggested that the HspB8-Bag3 complex might stimulate the degradation of Htt43Q by macroautophagy. This was confirmed by the observation that treatments with macroautophagy inhibitors significantly decreased HspB8- and Bag3-induced degradation of Htt43Q. We conclude that the HspB8 activity is intrinsically dependent on Bag3, a protein that may facilitate the disposal of doomed proteins by stimulating macroautophagy.
    URL, DOI BibTeX

    @article{Carra2008,
    	abstract = "Mutations in HspB8, a member of the B group of heat shock proteins (Hsp), have been associated with human neuromuscular disorders. However, the exact function of HspB8 is not yet clear. We previously demonstrated that overexpression of HspB8 in cultured cells prevents the accumulation of aggregation-prone proteins such as the polyglutamine protein Htt43Q. Here we report that HspB8 forms a stable complex with Bag3 in cells and that the formation of this complex is essential for the activity of HspB8. Bag3 overexpression resulted in the accelerated degradation of Htt43Q, whereas Bag3 knockdown prevented HspB8-induced Htt43Q degradation. Additionally, depleting Bag3 caused a reduction in the endogenous levels of LC3-II, a key molecule involved in macroautophagy, whereas overexpressing Bag3 or HspB8 stimulated the formation LC3-II. These results suggested that the HspB8-Bag3 complex might stimulate the degradation of Htt43Q by macroautophagy. This was confirmed by the observation that treatments with macroautophagy inhibitors significantly decreased HspB8- and Bag3-induced degradation of Htt43Q. We conclude that the HspB8 activity is intrinsically dependent on Bag3, a protein that may facilitate the disposal of doomed proteins by stimulating macroautophagy.",
    	author = "Carra, Serena and Seguin, Samuel J and Lambert, Herman and Landry, Jacques",
    	doi = "10.1074/jbc.M706304200",
    	issn = "0021-9258",
    	journal = "The Journal of biological chemistry",
    	keywords = "Adaptor Proteins, Signal Transducing,Adaptor Proteins, Signal Transducing: metabolism,Animals,Autophagy,Cell Line,Heat-Shock Proteins,Heat-Shock Proteins: metabolism,Humans,Microtubule-Associated Proteins,Microtubule-Associated Proteins: metabolism,Molecular Chaperones,Molecular Chaperones: metabolism,Mutant Proteins,Mutant Proteins: metabolism,Nerve Tissue Proteins,Nerve Tissue Proteins: metabolism,Nuclear Proteins,Nuclear Proteins: metabolism,Peptides,Peptides: metabolism,Protein Binding,Protein Processing, Post-Translational,Protein Structure, Quaternary,Protein-Serine-Threonine Kinases,Protein-Serine-Threonine Kinases: metabolism,Rats",
    	month = "jan",
    	number = 3,
    	pages = "1437--44",
    	pmid = 18006506,
    	title = "{HspB8 chaperone activity toward poly(Q)-containing proteins depends on its association with Bag3, a stimulator of macroautophagy.}",
    	url = "http://www.mendeley.com/research/hspb8-chaperone-activity-toward-polyqcontaining-proteins-depends-association-bag3-stimulator-macroau/",
    	volume = 283,
    	year = 2008
    }
    
  23. B Li, C C Smith, J M Laing, M D Gober, L Liu and L Aurelian.
    Overload of the heat-shock protein H11/HspB8 triggers melanoma cell apoptosis through activation of transforming growth factor-beta-activated kinase 1.. Oncogene 26(24):3521–31, May 2007.
    Abstract Molecular therapeutics is a recognized promising approach for melanoma, but relevant target genes remain elusive. We report that overload of the recently cloned H11/HspB8 induces apoptosis in 55% of examined melanoma cultures. Apoptosis was determined by activation of caspases-9 and -3 and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL), and was not seen in normal melanocytes. It was associated with H11/HspB8 complexation with transforming growth factor-beta-activated kinase (TAK) 1 and activation of TAK1 and p38 mitogen activated protein 3 kinases. TAK1 was not bound, nor activated by the H11/HspB8 mutant W51C, which has dominant antiapoptotic activity. beta-Catenin was phosphorylated by activated TAK1, inhibiting its nuclear accumulation and mictophthalmia-associated transcription factor and cyclin dependent kinase 2 expression. The dominant-negative TAK1 mutant K63W inhibited beta-catenin phosphorylation and caspase activation. The data indicate that H11/HspB8 overload causes melanoma growth arrest and apoptosis through TAK1 activation and suggest that H11/HspB8 is a promising molecular therapy target.
    URL, DOI BibTeX

    @article{Li2007,
    	abstract = "Molecular therapeutics is a recognized promising approach for melanoma, but relevant target genes remain elusive. We report that overload of the recently cloned H11/HspB8 induces apoptosis in 55{\%} of examined melanoma cultures. Apoptosis was determined by activation of caspases-9 and -3 and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL), and was not seen in normal melanocytes. It was associated with H11/HspB8 complexation with transforming growth factor-beta-activated kinase (TAK) 1 and activation of TAK1 and p38 mitogen activated protein 3 kinases. TAK1 was not bound, nor activated by the H11/HspB8 mutant W51C, which has dominant antiapoptotic activity. beta-Catenin was phosphorylated by activated TAK1, inhibiting its nuclear accumulation and mictophthalmia-associated transcription factor and cyclin dependent kinase 2 expression. The dominant-negative TAK1 mutant K63W inhibited beta-catenin phosphorylation and caspase activation. The data indicate that H11/HspB8 overload causes melanoma growth arrest and apoptosis through TAK1 activation and suggest that H11/HspB8 is a promising molecular therapy target.",
    	author = "Li, B and Smith, C C and Laing, J M and Gober, M D and Liu, L and Aurelian, L",
    	doi = "10.1038/sj.onc.1210145",
    	file = ":C$\backslash$:/Users/Riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Li et al. - 2007 - Overload of the heat-shock protein H11HspB8 triggers melanoma cell apoptosis through activation of transforming growt.pdf:pdf",
    	isbn = "0950-9232 (Print)$\backslash$r0950-9232 (Linking)",
    	issn = "0950-9232",
    	journal = "Oncogene",
    	keywords = "Apoptosis,Apoptosis: drug effects,Apoptosis: physiology,Caspases,Caspases: drug effects,Caspases: metabolism,Cell Nucleus,Cell Nucleus: metabolism,Cyclin-Dependent Kinase 2,Cyclin-Dependent Kinase 2: drug effects,Cyclin-Dependent Kinase 2: metabolism,Doxorubicin,Doxorubicin: pharmacology,Enzyme Activation,Heat-Shock Proteins,Heat-Shock Proteins: genetics,Heat-Shock Proteins: metabolism,Humans,MAP Kinase Kinase Kinases,MAP Kinase Kinase Kinases: metabolism,Melanocytes,Melanocytes: metabolism,Melanocytes: pathology,Melanoma,Melanoma: genetics,Melanoma: pathology,Microphthalmia-Associated Transcription Factor,Microphthalmia-Associated Transcription Factor: dr,Microphthalmia-Associated Transcription Factor: me,Phosphorylation,Protein-Serine-Threonine Kinases,Protein-Serine-Threonine Kinases: genetics,Protein-Serine-Threonine Kinases: metabolism,Tumor Cells, Cultured,beta Catenin,beta Catenin: drug effects,beta Catenin: metabolism,p38 Mitogen-Activated Protein Kinases,p38 Mitogen-Activated Protein Kinases: metabolism",
    	month = "may",
    	number = 24,
    	pages = "3521--31",
    	pmid = 17173073,
    	title = "{Overload of the heat-shock protein H11/HspB8 triggers melanoma cell apoptosis through activation of transforming growth factor-beta-activated kinase 1.}",
    	url = "http://www.mendeley.com/research/overload-heatshock-protein-h11hspb8-triggers-melanoma-cell-apoptosis-through-activation-transforming/",
    	volume = 26,
    	year = 2007
    }
    
  24. Micha M M Wilhelmus, Wilbert C Boelens, Irene Otte-Höller, Bram Kamps, Benno Kusters, Marion L C Maat-Schieman, Robert M W Waal and Marcel M Verbeek.
    Small heat shock protein HspB8: its distribution in Alzheimer's disease brains and its inhibition of amyloid-beta protein aggregation and cerebrovascular amyloid-beta toxicity.. Acta neuropathologica 111(2):139–49, March 2006.
    Abstract Alzheimer's disease (AD) is characterized by pathological lesions, such as senile plaques (SPs) and cerebral amyloid angiopathy (CAA), both predominantly consisting of a proteolytic cleavage product of the amyloid-beta precursor protein (APP), the amyloid-beta peptide (Abeta). CAA is also the major pathological lesion in hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D), caused by a mutation in the gene coding for the Abeta peptide. Several members of the small heat shock protein (sHsp) family, such as alphaB-crystallin, Hsp27, Hsp20 and HspB2, are associated with the pathological lesions of AD, and the direct interaction between sHsps and Abeta has been demonstrated in vitro. HspB8, also named Hsp22 of H11, is a recently discovered member of the sHsp family, which has chaperone activity and is observed in neuronal tissue. Furthermore, HspB8 affects protein aggregation, which has been shown by its ability to prevent formation of mutant huntingtin aggregates. The aim of this study was to investigate whether HspB8 is associated with the pathological lesions of AD and HCHWA-D and whether there are effects of HspB8 on Abeta aggregation and Abeta-mediated cytotoxicity. We observed the expression of HspB8 in classic SPs in AD brains. In addition, HspB8 was found in CAA in HCHWA-D brains, but not in AD brains. Direct interaction of HspB8 with Abeta(1-42), Abeta(1-40) and Abeta(1-40) with the Dutch mutation was demonstrated by surface plasmon resonance. Furthermore, co-incubation of HspB8 with D-Abeta(1-40) resulted in the complete inhibition of D-Abeta(1-40)-mediated death of cerebrovascular cells, likely mediated by a reduction in both the beta-sheet formation of D-Abeta(1-40) and its accumulation at the cell surface. In contrast, however, with Abeta(1-42), HspB8 neither affected beta-sheet formation nor Abeta-mediated cell death. We conclude that HspB8 might play an important role in regulating Abeta aggregation and, therefore, the development of classic SPs in AD and CAA in HCHWA-D.
    URL, DOI BibTeX

    @article{Wilhelmus2006,
    	abstract = "Alzheimer's disease (AD) is characterized by pathological lesions, such as senile plaques (SPs) and cerebral amyloid angiopathy (CAA), both predominantly consisting of a proteolytic cleavage product of the amyloid-beta precursor protein (APP), the amyloid-beta peptide (Abeta). CAA is also the major pathological lesion in hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D), caused by a mutation in the gene coding for the Abeta peptide. Several members of the small heat shock protein (sHsp) family, such as alphaB-crystallin, Hsp27, Hsp20 and HspB2, are associated with the pathological lesions of AD, and the direct interaction between sHsps and Abeta has been demonstrated in vitro. HspB8, also named Hsp22 of H11, is a recently discovered member of the sHsp family, which has chaperone activity and is observed in neuronal tissue. Furthermore, HspB8 affects protein aggregation, which has been shown by its ability to prevent formation of mutant huntingtin aggregates. The aim of this study was to investigate whether HspB8 is associated with the pathological lesions of AD and HCHWA-D and whether there are effects of HspB8 on Abeta aggregation and Abeta-mediated cytotoxicity. We observed the expression of HspB8 in classic SPs in AD brains. In addition, HspB8 was found in CAA in HCHWA-D brains, but not in AD brains. Direct interaction of HspB8 with Abeta(1-42), Abeta(1-40) and Abeta(1-40) with the Dutch mutation was demonstrated by surface plasmon resonance. Furthermore, co-incubation of HspB8 with D-Abeta(1-40) resulted in the complete inhibition of D-Abeta(1-40)-mediated death of cerebrovascular cells, likely mediated by a reduction in both the beta-sheet formation of D-Abeta(1-40) and its accumulation at the cell surface. In contrast, however, with Abeta(1-42), HspB8 neither affected beta-sheet formation nor Abeta-mediated cell death. We conclude that HspB8 might play an important role in regulating Abeta aggregation and, therefore, the development of classic SPs in AD and CAA in HCHWA-D.",
    	author = {Wilhelmus, Micha M M and Boelens, Wilbert C and Otte-H{\"{o}}ller, Irene and Kamps, Bram and Kusters, Benno and Maat-Schieman, Marion L C and de Waal, Robert M W and Verbeek, Marcel M},
    	doi = "10.1007/s00401-005-0030-z",
    	isbn = 3124366875,
    	issn = "0001-6322",
    	journal = "Acta neuropathologica",
    	keywords = "Aged,Aged, 80 and over,Alzheimer Disease,Alzheimer Disease: metabolism,Alzheimer Disease: pathology,Amyloid beta-Peptides,Amyloid beta-Peptides: antagonists {\&} inhibitors,Amyloid beta-Peptides: genetics,Amyloid beta-Peptides: metabolism,Amyloidosis,Amyloidosis: complications,Amyloidosis: genetics,Brain,Brain: metabolism,Cell Death,Cerebral Amyloid Angiopathy,Cerebral Amyloid Angiopathy: etiology,Cerebral Amyloid Angiopathy: prevention {\&} control,Cerebral Hemorrhage,Cerebral Hemorrhage: complications,Cerebral Hemorrhage: genetics,Heat-Shock Proteins,Heat-Shock Proteins: metabolism,Humans,Mutation,Peptide Fragments,Peptide Fragments: antagonists {\&} inhibitors,Peptide Fragments: metabolism,Plaque, Amyloid,Plaque, Amyloid: metabolism,Plaque, Amyloid: pathology,Protein-Serine-Threonine Kinases,Protein-Serine-Threonine Kinases: metabolism,Surface Plasmon Resonance,Tissue Distribution",
    	month = "mar",
    	number = 2,
    	pages = "139--49",
    	pmid = 16485107,
    	title = "{Small heat shock protein HspB8: its distribution in Alzheimer's disease brains and its inhibition of amyloid-beta protein aggregation and cerebrovascular amyloid-beta toxicity.}",
    	url = "http://www.mendeley.com/catalog/small-heat-shock-protein-hspb8-distribution-alzheimers-disease-brains-inhibition-amyloidbeta-protein/",
    	volume = 111,
    	year = 2006
    }
    
  25. Serena Carra, Mitchel Sivilotti, Aura T {Chávez Zobel}, Herman Lambert and Jacques Landry.
    HspB8, a small heat shock protein mutated in human neuromuscular disorders, has in vivo chaperone activity in cultured cells.. Human molecular genetics 14(12):1659–69, June 2005.
    Abstract The family of small heat shock proteins (sHsp) is composed of 10 members in mammals, four of which are found mutated in diseases associated with the accumulation of protein aggregates. Though many sHsp have demonstrated molecular chaperone activity in vitro in cell-free conditions, their activity in vivo in the normal cellular context remains unclear. In the present study, we investigated the capacity of the sHsp, HspB8/Hsp22, to prevent protein aggregation in the cells using the polyglutamine protein Htt43Q as a model. In control conditions, Htt43Q accumulated in perinuclear inclusions composed of SDS-insoluble aggregates. Co-transfected with Htt43Q, HspB8 became occasionally trapped within the inclusions; however, in most cells, HspB8 blocked inclusion formation. Biochemical analyses indicated that HspB8 inhibited the accumulation of SDS-insoluble Htt43Q as efficiently as Hsp40 which was taken as a positive control. Htt43Q then accumulated in the SDS-soluble fraction, provided that protein degradation was blocked by proteasome and autophagy inhibitors. In contrast, the other sHsp Hsp27/HspB1 and alphaB-crystallin/HspB5 had no effect. This suggested that HspB8 functions as a molecular chaperone, maintaining Htt43Q in a soluble state competent for rapid degradation. Analyses of Hsp27-HspB8 chimeric proteins indicated that the C-terminal domain of HspB8 contains the specific sequence necessary for chaperone activity. Missense mutations in this domain at lysine 141, which are found in human motor neuropathies, significantly reduced the chaperone activity of the protein. A decrease in the HspB8 chaperone activity may therefore contribute to the development of these diseases.
    URL, DOI BibTeX

    @article{Carra2005,
    	abstract = "The family of small heat shock proteins (sHsp) is composed of 10 members in mammals, four of which are found mutated in diseases associated with the accumulation of protein aggregates. Though many sHsp have demonstrated molecular chaperone activity in vitro in cell-free conditions, their activity in vivo in the normal cellular context remains unclear. In the present study, we investigated the capacity of the sHsp, HspB8/Hsp22, to prevent protein aggregation in the cells using the polyglutamine protein Htt43Q as a model. In control conditions, Htt43Q accumulated in perinuclear inclusions composed of SDS-insoluble aggregates. Co-transfected with Htt43Q, HspB8 became occasionally trapped within the inclusions; however, in most cells, HspB8 blocked inclusion formation. Biochemical analyses indicated that HspB8 inhibited the accumulation of SDS-insoluble Htt43Q as efficiently as Hsp40 which was taken as a positive control. Htt43Q then accumulated in the SDS-soluble fraction, provided that protein degradation was blocked by proteasome and autophagy inhibitors. In contrast, the other sHsp Hsp27/HspB1 and alphaB-crystallin/HspB5 had no effect. This suggested that HspB8 functions as a molecular chaperone, maintaining Htt43Q in a soluble state competent for rapid degradation. Analyses of Hsp27-HspB8 chimeric proteins indicated that the C-terminal domain of HspB8 contains the specific sequence necessary for chaperone activity. Missense mutations in this domain at lysine 141, which are found in human motor neuropathies, significantly reduced the chaperone activity of the protein. A decrease in the HspB8 chaperone activity may therefore contribute to the development of these diseases.",
    	author = "Carra, Serena and Sivilotti, Mitchel and {Ch{\'{a}}vez Zobel}, Aura T and Lambert, Herman and Landry, Jacques",
    	doi = "10.1093/hmg/ddi174",
    	issn = "0964-6906",
    	journal = "Human molecular genetics",
    	keywords = "Animals,Cells, Cultured,Citrate (si)-Synthase,Citrate (si)-Synthase: metabolism,Cricetinae,Cricetulus,Fibroblasts,Fibroblasts: cytology,Fibroblasts: metabolism,HSP27 Heat-Shock Proteins,Heat-Shock Proteins,Heat-Shock Proteins: genetics,Heat-Shock Proteins: metabolism,Hot Temperature,Humans,Lung,Lung: metabolism,Molecular Chaperones,Molecular Chaperones: metabolism,Mutation, Missense,Mutation, Missense: genetics,Neoplasm Proteins,Neoplasm Proteins: genetics,Neoplasm Proteins: metabolism,Neuromuscular Diseases,Neuromuscular Diseases: genetics,Neuromuscular Diseases: metabolism,Protein-Serine-Threonine Kinases,Protein-Serine-Threonine Kinases: genetics,Protein-Serine-Threonine Kinases: metabolism,alpha-Crystallin B Chain,alpha-Crystallin B Chain: genetics,alpha-Crystallin B Chain: metabolism",
    	month = "jun",
    	number = 12,
    	pages = "1659--69",
    	pmid = 15879436,
    	title = "{HspB8, a small heat shock protein mutated in human neuromuscular disorders, has in vivo chaperone activity in cultured cells.}",
    	url = "http://www.mendeley.com/research/hspb8-small-heat-shock-protein-mutated-human-neuromuscular-disorders-vivo-chaperone-activity-culture/",
    	volume = 14,
    	year = 2005
    }