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Here I will collect data concerning astrocyte toxicity to be used as a reference on my Big Picture mind map.

  1. Eugenia Ranno, Simona D'Antoni, Michela Spatuzza, Antonio Berretta, Floriana Laureanti, Carmela M Bonaccorso, Rosalia Pellitteri, Patrizia Longone, Alida Spalloni, Anand M Iyer, Eleonora Aronica and Maria Vincenza Catania.
    Endothelin-1 is over-expressed in amyotrophic lateral sclerosis and induces motor neuron cell death.. Neurobiology of disease 65:160–71, May 2014.
    Abstract Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive loss of motor neurons (MNs) and astrogliosis. Recent evidence suggests that factors secreted by activated astrocytes might contribute to degeneration of MNs. We focused on endothelin-1 (ET-1), a peptide which is strongly up-regulated in reactive astrocytes under different pathological conditions. We show that ET-1 is abundantly expressed by reactive astrocytes in the spinal cord of the SOD1-G93A mouse model and sporadic ALS patients. To test if ET-1 might play a role in degeneration of MNs, we investigated its effect on MN survival in an in vitro model of mixed rat spinal cord cultures (MSCs) enriched of astrocytes exhibiting a reactive phenotype. ET-1 exerted a toxic effect on MNs in a time- and concentration-dependent manner, with an exposure to 100-200nM ET-1 for 48h resulting in 40-50% MN cell death. Importantly, ET-1 did not induce MN degeneration when administered on cultures treated with AraC (5$\mu$M) or grown in a serum-free medium that did not favor astrocyte proliferation and reactivity. We found that both ETA and ETB receptors are enriched in astrocytes in MSCs. The ET-1 toxic effect was mimicked by ET-3 (100nM) and sarafotoxin S6c (10nM), two selective agonists of endothelin-B receptors, and was not additive with that of ET-3 suggesting the involvement of ETB receptors. Surprisingly, however, the ET-1 effect persisted in the presence of the ETB receptor antagonist BQ-788 (200nM-2$\mu$M) and was slightly reversed by the ETA receptor antagonist BQ-123 (2$\mu$M), suggesting an atypical pharmacological profile of the astrocytic receptors responsible for ET-1 toxicity. The ET-1 effect was not undone by the ionotropic glutamate receptor AMPA antagonist GYKI 52466 (20$\mu$M), indicating that it is not caused by an increased glutamate release. Conversely, a 48-hour ET-1 treatment increased MN cell death induced by acute exposure to AMPA (50$\mu$M), which is indicative of two distinct pathways leading to neuronal death. Altogether these results indicate that ET-1 exerts a toxic effect on cultured MNs through mechanisms mediated by reactive astrocytes and suggest that ET-1 may contribute to MN degeneration in ALS. Thus, a treatment aimed at lowering ET-1 levels or antagonizing its effect might be envisaged as a potential therapeutic strategy to slow down MN degeneration in this devastating disease.
    URL, DOI BibTeX

    @article{Ranno2014,
    	abstract = "Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive loss of motor neurons (MNs) and astrogliosis. Recent evidence suggests that factors secreted by activated astrocytes might contribute to degeneration of MNs. We focused on endothelin-1 (ET-1), a peptide which is strongly up-regulated in reactive astrocytes under different pathological conditions. We show that ET-1 is abundantly expressed by reactive astrocytes in the spinal cord of the SOD1-G93A mouse model and sporadic ALS patients. To test if ET-1 might play a role in degeneration of MNs, we investigated its effect on MN survival in an in vitro model of mixed rat spinal cord cultures (MSCs) enriched of astrocytes exhibiting a reactive phenotype. ET-1 exerted a toxic effect on MNs in a time- and concentration-dependent manner, with an exposure to 100-200nM ET-1 for 48h resulting in 40-50\% MN cell death. Importantly, ET-1 did not induce MN degeneration when administered on cultures treated with AraC (5$\mu$M) or grown in a serum-free medium that did not favor astrocyte proliferation and reactivity. We found that both ETA and ETB receptors are enriched in astrocytes in MSCs. The ET-1 toxic effect was mimicked by ET-3 (100nM) and sarafotoxin S6c (10nM), two selective agonists of endothelin-B receptors, and was not additive with that of ET-3 suggesting the involvement of ETB receptors. Surprisingly, however, the ET-1 effect persisted in the presence of the ETB receptor antagonist BQ-788 (200nM-2$\mu$M) and was slightly reversed by the ETA receptor antagonist BQ-123 (2$\mu$M), suggesting an atypical pharmacological profile of the astrocytic receptors responsible for ET-1 toxicity. The ET-1 effect was not undone by the ionotropic glutamate receptor AMPA antagonist GYKI 52466 (20$\mu$M), indicating that it is not caused by an increased glutamate release. Conversely, a 48-hour ET-1 treatment increased MN cell death induced by acute exposure to AMPA (50$\mu$M), which is indicative of two distinct pathways leading to neuronal death. Altogether these results indicate that ET-1 exerts a toxic effect on cultured MNs through mechanisms mediated by reactive astrocytes and suggest that ET-1 may contribute to MN degeneration in ALS. Thus, a treatment aimed at lowering ET-1 levels or antagonizing its effect might be envisaged as a potential therapeutic strategy to slow down MN degeneration in this devastating disease.",
    	author = "Ranno, Eugenia and D'Antoni, Simona and Spatuzza, Michela and Berretta, Antonio and Laureanti, Floriana and Bonaccorso, Carmela M and Pellitteri, Rosalia and Longone, Patrizia and Spalloni, Alida and Iyer, Anand M and Aronica, Eleonora and Catania, Maria Vincenza",
    	doi = "10.1016/j.nbd.2014.01.002",
    	issn = "1095-953X",
    	journal = "Neurobiology of disease",
    	month = "may",
    	pages = "160--71",
    	pmid = 24423643,
    	title = "{Endothelin-1 is over-expressed in amyotrophic lateral sclerosis and induces motor neuron cell death.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/24423643",
    	volume = 65,
    	year = 2014
    }
    
  2. Leslie I Grad, Justin J Yerbury, Bradley J Turner, William C Guest, Edward Pokrishevsky, Megan A O'Neill, Anat Yanai, Judith M Silverman, Rafaa Zeineddine, Lisa Corcoran, Janet R Kumita, Leila M Luheshi, Masoud Yousefi, Bradley M Coleman, Andrew F Hill, Steven S Plotkin, Ian R Mackenzie and Neil R Cashman.
    Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and -independent mechanisms.. Proceedings of the National Academy of Sciences of the United States of America 111(9):3620–5, 2014.
    Abstract Amyotrophic lateral sclerosis (ALS) is predominantly sporadic, but associated with heritable genetic mutations in 5-10% of cases, including those in Cu/Zn superoxide dismutase (SOD1). We previously showed that misfolding of SOD1 can be transmitted to endogenous human wild-type SOD1 (HuWtSOD1) in an intracellular compartment. Using NSC-34 motor neuron-like cells, we now demonstrate that misfolded mutant and HuWtSOD1 can traverse between cells via two nonexclusive mechanisms: protein aggregates released from dying cells and taken up by macropinocytosis, and exosomes secreted from living cells. Furthermore, once HuWtSOD1 propagation has been established, misfolding of HuWtSOD1 can be efficiently and repeatedly propagated between HEK293 cell cultures via conditioned media over multiple passages, and to cultured mouse primary spinal cord cells transgenically expressing HuWtSOD1, but not to cells derived from nontransgenic littermates. Conditioned media transmission of HuWtSOD1 misfolding in HEK293 cells is blocked by HuWtSOD1 siRNA knockdown, consistent with human SOD1 being a substrate for conversion, and attenuated by ultracentrifugation or incubation with SOD1 misfolding-specific antibodies, indicating a relatively massive transmission particle which possesses antibody-accessible SOD1. Finally, misfolded and protease-sensitive HuWtSOD1 comprises up to 4% of total SOD1 in spinal cords of patients with sporadic ALS (SALS). Propagation of HuWtSOD1 misfolding, and its subsequent cell-to-cell transmission, is thus a candidate process for the molecular pathogenesis of SALS, which may provide novel treatment and biomarker targets for this devastating disease.
    URL, DOI BibTeX

    @article{Grad2014,
    	abstract = "Amyotrophic lateral sclerosis (ALS) is predominantly sporadic, but associated with heritable genetic mutations in 5-10\% of cases, including those in Cu/Zn superoxide dismutase (SOD1). We previously showed that misfolding of SOD1 can be transmitted to endogenous human wild-type SOD1 (HuWtSOD1) in an intracellular compartment. Using NSC-34 motor neuron-like cells, we now demonstrate that misfolded mutant and HuWtSOD1 can traverse between cells via two nonexclusive mechanisms: protein aggregates released from dying cells and taken up by macropinocytosis, and exosomes secreted from living cells. Furthermore, once HuWtSOD1 propagation has been established, misfolding of HuWtSOD1 can be efficiently and repeatedly propagated between HEK293 cell cultures via conditioned media over multiple passages, and to cultured mouse primary spinal cord cells transgenically expressing HuWtSOD1, but not to cells derived from nontransgenic littermates. Conditioned media transmission of HuWtSOD1 misfolding in HEK293 cells is blocked by HuWtSOD1 siRNA knockdown, consistent with human SOD1 being a substrate for conversion, and attenuated by ultracentrifugation or incubation with SOD1 misfolding-specific antibodies, indicating a relatively massive transmission particle which possesses antibody-accessible SOD1. Finally, misfolded and protease-sensitive HuWtSOD1 comprises up to 4\% of total SOD1 in spinal cords of patients with sporadic ALS (SALS). Propagation of HuWtSOD1 misfolding, and its subsequent cell-to-cell transmission, is thus a candidate process for the molecular pathogenesis of SALS, which may provide novel treatment and biomarker targets for this devastating disease.",
    	author = "Grad, Leslie I and Yerbury, Justin J and Turner, Bradley J and Guest, William C and Pokrishevsky, Edward and O'Neill, Megan A and Yanai, Anat and Silverman, Judith M and Zeineddine, Rafaa and Corcoran, Lisa and Kumita, Janet R and Luheshi, Leila M and Yousefi, Masoud and Coleman, Bradley M and Hill, Andrew F and Plotkin, Steven S and Mackenzie, Ian R and Cashman, Neil R",
    	doi = "10.1073/pnas.1312245111",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Grad et al. - 2014 - Intercellular propagated misfolding of wild-type CuZn superoxide dismutase occurs via exosome-dependent and -indepe.pdf:pdf",
    	issn = "1091-6490",
    	journal = "Proceedings of the National Academy of Sciences of the United States of America",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: metabolism,Amyotrophic Lateral Sclerosis: physiopathology,Animals,Cell Line,Electrophoresis, Polyacrylamide Gel,Exosomes,Exosomes: metabolism,Humans,Mice,Microscopy, Electron,Pinocytosis,Pinocytosis: physiology,Protein Folding,RNA Interference,RNA, Small Interfering,RNA, Small Interfering: genetics,Superoxide Dismutase,Superoxide Dismutase: chemistry,Superoxide Dismutase: metabolism",
    	month = "",
    	number = 9,
    	pages = "3620--5",
    	pmid = 24550511,
    	title = "{Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and -independent mechanisms.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3948312\&tool=pmcentrez\&rendertype=abstract",
    	volume = 111,
    	year = 2014
    }
    
  3. Manuela Basso, Silvia Pozzi, Massimo Tortarolo, Fabio Fiordaliso, Cinzia Bisighini, Laura Pasetto, Gabriella Spaltro, Dario Lidonnici, Francesco Gensano, Elisa Battaglia, Caterina Bendotti and Valentina Bonetto.
    Mutant copper-zinc superoxide dismutase (SOD1) induces protein secretion pathway alterations and exosome release in astrocytes: implications for disease spreading and motor neuron pathology in amyotrophic lateral sclerosis.. The Journal of biological chemistry 288(22):15699–711, 2013.
    Abstract Amyotrophic lateral sclerosis is the most common motor neuron disease and is still incurable. The mechanisms leading to the selective motor neuron vulnerability are still not known. The interplay between motor neurons and astrocytes is crucial in the outcome of the disease. We show that mutant copper-zinc superoxide dismutase (SOD1) overexpression in primary astrocyte cultures is associated with decreased levels of proteins involved in secretory pathways. This is linked to a general reduction of total secreted proteins, except for specific enrichment in a number of proteins in the media, such as mutant SOD1 and valosin-containing protein (VCP)/p97. Because there was also an increase in exosome release, we can deduce that astrocytes expressing mutant SOD1 activate unconventional secretory pathways, possibly as a protective mechanism. This may help limit the formation of intracellular aggregates and overcome mutant SOD1 toxicity. We also found that astrocyte-derived exosomes efficiently transfer mutant SOD1 to spinal neurons and induce selective motor neuron death. We conclude that the expression of mutant SOD1 has a substantial impact on astrocyte protein secretion pathways, contributing to motor neuron pathology and disease spread.
    URL, DOI BibTeX

    @article{Basso2013,
    	abstract = "Amyotrophic lateral sclerosis is the most common motor neuron disease and is still incurable. The mechanisms leading to the selective motor neuron vulnerability are still not known. The interplay between motor neurons and astrocytes is crucial in the outcome of the disease. We show that mutant copper-zinc superoxide dismutase (SOD1) overexpression in primary astrocyte cultures is associated with decreased levels of proteins involved in secretory pathways. This is linked to a general reduction of total secreted proteins, except for specific enrichment in a number of proteins in the media, such as mutant SOD1 and valosin-containing protein (VCP)/p97. Because there was also an increase in exosome release, we can deduce that astrocytes expressing mutant SOD1 activate unconventional secretory pathways, possibly as a protective mechanism. This may help limit the formation of intracellular aggregates and overcome mutant SOD1 toxicity. We also found that astrocyte-derived exosomes efficiently transfer mutant SOD1 to spinal neurons and induce selective motor neuron death. We conclude that the expression of mutant SOD1 has a substantial impact on astrocyte protein secretion pathways, contributing to motor neuron pathology and disease spread.",
    	author = "Basso, Manuela and Pozzi, Silvia and Tortarolo, Massimo and Fiordaliso, Fabio and Bisighini, Cinzia and Pasetto, Laura and Spaltro, Gabriella and Lidonnici, Dario and Gensano, Francesco and Battaglia, Elisa and Bendotti, Caterina and Bonetto, Valentina",
    	doi = "10.1074/jbc.M112.425066",
    	issn = "1083-351X",
    	journal = "The Journal of biological chemistry",
    	keywords = "Adenosine Triphosphatases,Adenosine Triphosphatases: genetics,Adenosine Triphosphatases: metabolism,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: enzymology,Amyotrophic Lateral Sclerosis: genetics,Amyotrophic Lateral Sclerosis: pathology,Animals,Astrocytes,Astrocytes: enzymology,Astrocytes: pathology,Cell Cycle Proteins,Cell Cycle Proteins: genetics,Cell Cycle Proteins: metabolism,Cell Death,Cell Death: genetics,Exosomes,Exosomes: enzymology,Exosomes: genetics,Exosomes: pathology,Humans,Mice,Mice, Transgenic,Motor Neurons,Motor Neurons: enzymology,Motor Neurons: pathology,Mutation,Nerve Tissue Proteins,Nerve Tissue Proteins: genetics,Nerve Tissue Proteins: metabolism,Superoxide Dismutase,Superoxide Dismutase: genetics,Superoxide Dismutase: secretion",
    	month = "",
    	number = 22,
    	pages = "15699--711",
    	pmid = 23592792,
    	title = "{Mutant copper-zinc superoxide dismutase (SOD1) induces protein secretion pathway alterations and exosome release in astrocytes: implications for disease spreading and motor neuron pathology in amyotrophic lateral sclerosis.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3668729\&tool=pmcentrez\&rendertype=abstract",
    	volume = 288,
    	year = 2013
    }
    
  4. Catarina Gomes, Sascha Keller, Peter Altevogt and Júlia Costa.
    Evidence for secretion of Cu,Zn superoxide dismutase via exosomes from a cell model of amyotrophic lateral sclerosis.. Neuroscience letters 428(1):43–6, 2007.
    Abstract A familial form of the neurodegenerative disease amyotrophic lateral sclerosis (ALS), is caused by dominant mutations in the cytosolic Cu,Zn superoxide dismutase (SOD1). There has been evidence for secretion of SOD1, by an unknown mechanism. In this work stable mouse motor neuron-like NSC-34 cells overexpressing human SOD1 wild-type hSOD1(wt) (NSC-34/hSOD1(wt)) and mutant hSOD1(G93A) (NSC-34/hSOD1(G93A)) have been used as an ALS cell model. SOD1 was found to be secreted in association with a membrane fraction that pelleted at 100,000xg. Sucrose density gradient separation of this fraction showed that wild-type and mutant SOD1 were found between 0.5 and 1.16M sucrose and co-localized with the exosomal marker CD9. Therefore, SOD1 secretion occurred via exosomes. p115 a cytosolic and Golgi apparatus (GA) protein involved in vesicle tethering was also found in exosomes, contrary to the endoplasmic reticulum protein calnexin. SOD1 secretion mediated by exosomes could explain cell-to-cell transfer of mutant toxicity.
    URL, DOI BibTeX

    @article{Gomes2007,
    	abstract = "A familial form of the neurodegenerative disease amyotrophic lateral sclerosis (ALS), is caused by dominant mutations in the cytosolic Cu,Zn superoxide dismutase (SOD1). There has been evidence for secretion of SOD1, by an unknown mechanism. In this work stable mouse motor neuron-like NSC-34 cells overexpressing human SOD1 wild-type hSOD1(wt) (NSC-34/hSOD1(wt)) and mutant hSOD1(G93A) (NSC-34/hSOD1(G93A)) have been used as an ALS cell model. SOD1 was found to be secreted in association with a membrane fraction that pelleted at 100,000xg. Sucrose density gradient separation of this fraction showed that wild-type and mutant SOD1 were found between 0.5 and 1.16M sucrose and co-localized with the exosomal marker CD9. Therefore, SOD1 secretion occurred via exosomes. p115 a cytosolic and Golgi apparatus (GA) protein involved in vesicle tethering was also found in exosomes, contrary to the endoplasmic reticulum protein calnexin. SOD1 secretion mediated by exosomes could explain cell-to-cell transfer of mutant toxicity.",
    	author = "Gomes, Catarina and Keller, Sascha and Altevogt, Peter and Costa, J\'{u}lia",
    	doi = "10.1016/j.neulet.2007.09.024",
    	issn = "0304-3940",
    	journal = "Neuroscience letters",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: enzymology,Amyotrophic Lateral Sclerosis: pathology,Animals,Cell Fractionation,Cell Fractionation: methods,Cell Line, Transformed,Disease Models, Animal,Humans,Mice,Motor Neurons,Motor Neurons: enzymology,Motor Neurons: ultrastructure,Mutation,Mutation: physiology,Secretory Vesicles,Secretory Vesicles: enzymology,Superoxide Dismutase,Superoxide Dismutase: secretion",
    	month = "",
    	number = 1,
    	pages = "43--6",
    	pmid = 17942226,
    	title = "{Evidence for secretion of Cu,Zn superoxide dismutase via exosomes from a cell model of amyotrophic lateral sclerosis.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/17942226",
    	volume = 428,
    	year = 2007
    }
    
  5. Luis H Barbeito, Mariana Pehar, Patricia Cassina, Marcelo R Vargas, Hugo Peluffo, Liliana Viera, Alvaro G Estévez and Joseph S Beckman.
    A role for astrocytes in motor neuron loss in amyotrophic lateral sclerosis.. Brain research. Brain research reviews 47(1-3):263–74, 2004.
    Abstract A strong glial reaction typically surrounds the affected upper and lower motor neurons and degenerating descending tracts of ALS patients. Reactive astrocytes in ALS contain protein inclusions, express inflammatory makers such as the inducible forms of nitric oxide synthase (iNOS) and cyclooxygenase (COX-2), display nitrotyrosine immunoreactivity and downregulate the glutamate transporter EAAT2. In this review, we discuss the evidence sustaining an active role for astrocytes in the induction and propagation of motor neuron loss in ALS. Available evidence supports the view that glial activation could be initiated by proinflammatory mediators secreted by motor neurons in response to injury, axotomy or muscular pathology. In turn, reactive astrocytes produce nitric oxide and peroxynitrite, which cause mitochondrial damage in cultured neurons and trigger apoptosis in motor neurons. Astrocytes may also contribute to the excitotoxic damage of motor neurons by decreasing glutamate transport or actively releasing the excitotoxic amino acid. In addition, reactive astrocytes secrete pro-apoptotic mediators, such as nerve growth factor (NGF) or Fas-ligand, a mechanism that may serve to eliminate vulnerable motor neurons. The comprehensive understanding of the interactions between motor neurons and glia in ALS may lead to a more accurate theory of the pathogenesis of the disease.
    URL, DOI BibTeX

    @article{Barbeito2004,
    	abstract = "A strong glial reaction typically surrounds the affected upper and lower motor neurons and degenerating descending tracts of ALS patients. Reactive astrocytes in ALS contain protein inclusions, express inflammatory makers such as the inducible forms of nitric oxide synthase (iNOS) and cyclooxygenase (COX-2), display nitrotyrosine immunoreactivity and downregulate the glutamate transporter EAAT2. In this review, we discuss the evidence sustaining an active role for astrocytes in the induction and propagation of motor neuron loss in ALS. Available evidence supports the view that glial activation could be initiated by proinflammatory mediators secreted by motor neurons in response to injury, axotomy or muscular pathology. In turn, reactive astrocytes produce nitric oxide and peroxynitrite, which cause mitochondrial damage in cultured neurons and trigger apoptosis in motor neurons. Astrocytes may also contribute to the excitotoxic damage of motor neurons by decreasing glutamate transport or actively releasing the excitotoxic amino acid. In addition, reactive astrocytes secrete pro-apoptotic mediators, such as nerve growth factor (NGF) or Fas-ligand, a mechanism that may serve to eliminate vulnerable motor neurons. The comprehensive understanding of the interactions between motor neurons and glia in ALS may lead to a more accurate theory of the pathogenesis of the disease.",
    	author = "Barbeito, Luis H and Pehar, Mariana and Cassina, Patricia and Vargas, Marcelo R and Peluffo, Hugo and Viera, Liliana and Est\'{e}vez, Alvaro G and Beckman, Joseph S",
    	doi = "10.1016/j.brainresrev.2004.05.003",
    	journal = "Brain research. Brain research reviews",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: metabolism,Amyotrophic Lateral Sclerosis: pathology,Amyotrophic Lateral Sclerosis: physiopathology,Animals,Apoptosis,Apoptosis: physiology,Astrocytes,Astrocytes: immunology,Astrocytes: metabolism,Cell Communication,Cell Communication: physiology,Gliosis,Gliosis: metabolism,Gliosis: pathology,Gliosis: physiopathology,Glutamic Acid,Glutamic Acid: metabolism,Humans,Inflammation Mediators,Inflammation Mediators: metabolism,Motor Neurons,Motor Neurons: metabolism,Motor Neurons: pathology",
    	month = "",
    	number = "1-3",
    	pages = "263--74",
    	pmid = 15572176,
    	title = "{A role for astrocytes in motor neuron loss in amyotrophic lateral sclerosis.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/15572176",
    	volume = 47,
    	year = 2004
    }
    
  6. Seung H Kim, Jenny S Henkel, David R Beers, Ihsan S Sengun, Ericka P Simpson, Clay J Goodman, Jozsef I Engelhardt, László Siklós and Stanley H Appel.
    PARP expression is increased in astrocytes but decreased in motor neurons in the spinal cord of sporadic ALS patients.. Journal of neuropathology and experimental neurology 62(1):88–103, 2003.
    Abstract The evidence for increased oxidative stress and DNA damage in amyotrophic lateral sclerosis (ALS) prompted studies to determine if the expression of poly(ADP-ribose) polymerase (PARP) is increased in ALS. Using Western analyses of postmortem tissue, we demonstrated that PARP-immunoreactivity (PARP-IR) was increased 3-fold in spinal cord tissues of sporadic ALS (sALS) patients compared with non-neurological disease controls. Despite the increased PARP-IR, PARP mRNA expression was not increased significantly. Immunohistochemical analyses revealed PARP-IR was increased in both white and gray matter of sALS spinal cord. While PARP-IR was predominantly seen in astrocytes, large motor neurons displayed reduced staining compared with controls. This result contrasts sharply to the staining of Alzheimer and MPTP-induced Parkinson diseased tissue, where poly(ADP-ribose) (PAR)-IR was seen mostly in neurons, with little astrocytic staining. PARP-IR was increased in the pellet fraction of sALS homogenates compared with control homogenates, representing potential PARP binding to chromatin or membranes and suggesting a possible mechanism of PARP stabilization. The present results demonstrate glial alterations in sALS spinal cord tissue and support the role of glial alterations in sALS pathogenesis. Additionally, these results demonstrate differences in sALS spinal motor neurons and astrocytes compared to brain neurons and astrocytes in Alzheimer disease and MPTP-induced Parkinson disease despite the presence of markers for oxidative stress in all 3 diseases.
    URL BibTeX

    @article{Kim2003,
    	abstract = "The evidence for increased oxidative stress and DNA damage in amyotrophic lateral sclerosis (ALS) prompted studies to determine if the expression of poly(ADP-ribose) polymerase (PARP) is increased in ALS. Using Western analyses of postmortem tissue, we demonstrated that PARP-immunoreactivity (PARP-IR) was increased 3-fold in spinal cord tissues of sporadic ALS (sALS) patients compared with non-neurological disease controls. Despite the increased PARP-IR, PARP mRNA expression was not increased significantly. Immunohistochemical analyses revealed PARP-IR was increased in both white and gray matter of sALS spinal cord. While PARP-IR was predominantly seen in astrocytes, large motor neurons displayed reduced staining compared with controls. This result contrasts sharply to the staining of Alzheimer and MPTP-induced Parkinson diseased tissue, where poly(ADP-ribose) (PAR)-IR was seen mostly in neurons, with little astrocytic staining. PARP-IR was increased in the pellet fraction of sALS homogenates compared with control homogenates, representing potential PARP binding to chromatin or membranes and suggesting a possible mechanism of PARP stabilization. The present results demonstrate glial alterations in sALS spinal cord tissue and support the role of glial alterations in sALS pathogenesis. Additionally, these results demonstrate differences in sALS spinal motor neurons and astrocytes compared to brain neurons and astrocytes in Alzheimer disease and MPTP-induced Parkinson disease despite the presence of markers for oxidative stress in all 3 diseases.",
    	author = "Kim, Seung H and Henkel, Jenny S and Beers, David R and Sengun, Ihsan S and Simpson, Ericka P and Goodman, J Clay and Engelhardt, Jozsef I and Sikl\'{o}s, L\'{a}szl\'{o} and Appel, Stanley H",
    	issn = "0022-3069",
    	journal = "Journal of neuropathology and experimental neurology",
    	keywords = "Adult,Aged,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: enzymology,Amyotrophic Lateral Sclerosis: pathology,Astrocytes,Astrocytes: enzymology,Astrocytes: pathology,Female,Gene Expression,Gene Expression: physiology,Humans,Male,Middle Aged,Motor Neurons,Motor Neurons: enzymology,Motor Neurons: pathology,Poly(ADP-ribose) Polymerases,Poly(ADP-ribose) Polymerases: analysis,Poly(ADP-ribose) Polymerases: biosynthesis,Solubility,Spinal Cord,Spinal Cord: enzymology,Spinal Cord: pathology",
    	month = "",
    	number = 1,
    	pages = "88--103",
    	pmid = 12528821,
    	title = "{PARP expression is increased in astrocytes but decreased in motor neurons in the spinal cord of sporadic ALS patients.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/12528821",
    	volume = 62,
    	year = 2003
    }