Visitor counter, Heat Map, Conversion tracking, Search Rank

My current (Jun 12 2014) view is that misfolding of a protein - SOD1, TDP-43 or FUS depending on which flavour of ALS you have - is the central process in the disease. In order to find out how it connects to the other known anomalies it would be paramount to find an answer to one specific question:

does the misfolding spread directly through a physical template (as is the case in prion diseases) or indirectly by altering the conditions in the endoplasmic reticulum e.g. through mitochondrial dysfunction?

In the former case, there is no other way to intervene than to attack the misfolded proteins directly, as all other anomalies are just a downstream consequence of the propagating protein misfolding, not part of the core disease process that causes the progression.

If the latter hypothesis is true, there are more options. If the misfolding is caused by lack of energy in the ER, the lack of energy by mitochondrial dysfunction and the mitochondrial dysfunction by the misfolded proteins, strategies aimed at improving mitochondrial function may help halt the vicious circle. 

 

UPDATE SEP 2015:

Some recent papers suggest that loss of TDP-43 from the nucleus would cause the cell to die via loss-of-function (prevention of cryptic exons from being decoded). This would mean either excessive traffic away from the nucleus or diminished traffic into it. Prion-like misfolding into aggregates would provide the required mechanism to prevent TDP-43 from entering the nucleus.

 

  1. Shynrye Lee and Hyung-Jun Kim.
    Prion-like Mechanism in Amyotrophic Lateral Sclerosis: are Protein Aggregates the Key?. Experimental neurobiology 24(1):1–7, March 2015.
    Abstract ALS is a fatal adult-onset motor neuron disease. Motor neurons in the cortex, brain stem and spinal cord gradually degenerate in ALS patients, and most ALS patients die within 3\~5 years of disease onset due to respiratory failure. The major pathological hallmark of ALS is abnormal accumulation of protein inclusions containing TDP-43, FUS or SOD1 protein. Moreover, the focality of clinical onset and regional spreading of neurodegeneration are typical features of ALS. These clinical data indicate that neurodegeneration in ALS is an orderly propagating process, which seems to share the signature of a seeded self-propagation with pathogenic prion proteins. In vitro and cell line experimental evidence suggests that SOD1, TDP-43 and FUS form insoluble fibrillar aggregates. Notably, these protein fibrillar aggregates can act as seeds to trigger the aggregation of native counterparts. Collectively, a self-propagation mechanism similar to prion replication and spreading may underlie the pathology of ALS. In this review, we will briefly summarize recent evidence to support the prion-like properties of major ALS-associated proteins and discuss the possible therapeutic strategies for ALS based on a prion-like mechanism.
    URL, DOI BibTeX

    @article{Lee2015,
    	abstract = "ALS is a fatal adult-onset motor neuron disease. Motor neurons in the cortex, brain stem and spinal cord gradually degenerate in ALS patients, and most ALS patients die within 3\~{}5 years of disease onset due to respiratory failure. The major pathological hallmark of ALS is abnormal accumulation of protein inclusions containing TDP-43, FUS or SOD1 protein. Moreover, the focality of clinical onset and regional spreading of neurodegeneration are typical features of ALS. These clinical data indicate that neurodegeneration in ALS is an orderly propagating process, which seems to share the signature of a seeded self-propagation with pathogenic prion proteins. In vitro and cell line experimental evidence suggests that SOD1, TDP-43 and FUS form insoluble fibrillar aggregates. Notably, these protein fibrillar aggregates can act as seeds to trigger the aggregation of native counterparts. Collectively, a self-propagation mechanism similar to prion replication and spreading may underlie the pathology of ALS. In this review, we will briefly summarize recent evidence to support the prion-like properties of major ALS-associated proteins and discuss the possible therapeutic strategies for ALS based on a prion-like mechanism.",
    	author = "Lee, Shynrye and Kim, Hyung-Jun",
    	doi = "10.5607/en.2015.24.1.1",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Lee, Kim - 2015 - Prion-like Mechanism in Amyotrophic Lateral Sclerosis are Protein Aggregates the Key.pdf:pdf",
    	issn = "1226-2560",
    	journal = "Experimental neurobiology",
    	month = "mar",
    	number = 1,
    	pages = "1--7",
    	pmid = 25792864,
    	title = "{Prion-like Mechanism in Amyotrophic Lateral Sclerosis: are Protein Aggregates the Key?}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4363329\&tool=pmcentrez\&rendertype=abstract",
    	volume = 24,
    	year = 2015
    }
    
  2. Phillip Smethurst, Katie Claire Louise Sidle and John Hardy.
    Review: Prion-like mechanisms of transactive response DNA binding protein of 43 kDa (TDP-43) in amyotrophic lateral sclerosis (ALS).. Neuropathology and applied neurobiology 41(5):578–97, 2015.
    Abstract Amyotrophic lateral sclerosis (ALS) is a fatal devastating neurodegenerative disorder which predominantly affects the motor neurons in the brain and spinal cord. The death of the motor neurons in ALS causes subsequent muscle atrophy, paralysis and eventual death. Clinical and biological evidence now demonstrates that ALS has many similarities to prion disease in terms of disease onset, phenotype variability and progressive spread. The pathognomonic ubiquitinated inclusions deposited in the neurons and glial cells in brains and spinal cords of patients with ALS and fronto-temporal lobar degeneration with ubiquitinated inclusions contain aggregated transactive response DNA binding protein of 43 kDa (TDP-43), and evidence now suggests that TDP-43 has cellular prion-like properties. The cellular mechanisms of prion protein misfolding and aggregation are thought to be responsible for the characteristics of prion disease. Therefore, there is a strong mechanistic basis for a prion-like behaviour of the TDP-43 protein being responsible for some characteristics of ALS. In this review, we compare the prion-like mechanisms of TDP-43 to the clinical and biological nature of ALS in order to investigate how this protein could be responsible for some of the characteristic properties of the disease.
    URL, DOI BibTeX

    @article{Smethurst2015,
    	abstract = "Amyotrophic lateral sclerosis (ALS) is a fatal devastating neurodegenerative disorder which predominantly affects the motor neurons in the brain and spinal cord. The death of the motor neurons in ALS causes subsequent muscle atrophy, paralysis and eventual death. Clinical and biological evidence now demonstrates that ALS has many similarities to prion disease in terms of disease onset, phenotype variability and progressive spread. The pathognomonic ubiquitinated inclusions deposited in the neurons and glial cells in brains and spinal cords of patients with ALS and fronto-temporal lobar degeneration with ubiquitinated inclusions contain aggregated transactive response DNA binding protein of 43 kDa (TDP-43), and evidence now suggests that TDP-43 has cellular prion-like properties. The cellular mechanisms of prion protein misfolding and aggregation are thought to be responsible for the characteristics of prion disease. Therefore, there is a strong mechanistic basis for a prion-like behaviour of the TDP-43 protein being responsible for some characteristics of ALS. In this review, we compare the prion-like mechanisms of TDP-43 to the clinical and biological nature of ALS in order to investigate how this protein could be responsible for some of the characteristic properties of the disease.",
    	author = "Smethurst, Phillip and Sidle, Katie Claire Louise and Hardy, John",
    	doi = "10.1111/nan.12206",
    	issn = "1365-2990",
    	journal = "Neuropathology and applied neurobiology",
    	month = "",
    	number = 5,
    	pages = "578--97",
    	pmid = 25487060,
    	title = "{Review: Prion-like mechanisms of transactive response DNA binding protein of 43 kDa (TDP-43) in amyotrophic lateral sclerosis (ALS).}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/25487060",
    	volume = 41,
    	year = 2015
    }
    
  3. Leslie I Grad, Sarah M Fernando and Neil R Cashman.
    From molecule to molecule and cell to cell: prion-like mechanisms in amyotrophic lateral sclerosis.. Neurobiology of disease 77:257–65, 2015.
    Abstract Prions, self-proliferating infectious agents consisting of misfolded protein, are most often associated with aggressive neurodegenerative diseases in animals and humans. Akin to the contiguous spread of a living pathogen, the prion paradigm provides a mechanism by which a mutant or wild-type misfolded protein can dominate pathogenesis through self-propagating protein misfolding, and subsequently spread from region to region through the central nervous system. The prion diseases, along with more common neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and the tauopathies belong to a larger group of protein misfolding disorders termed proteinopathies that feature aberrant misfolding and aggregation of specific proteins. Amyotrophic lateral sclerosis (ALS), a lethal disease characterized by progressive degeneration of motor neurons is currently understood as a classical proteinopathy; the disease is typified by the formation of inclusions consisting of aggregated protein within motor neurons that contribute to neurotoxicity. It is well established that misfolded/aggregated proteins such as SOD1 and TDP-43 contribute to the toxicity of motor neurons and play a prominent role in the pathology of ALS. Recent work has identified propagated protein misfolding properties in both mutant and wild-type SOD1, and to a lesser extent TDP-43, which may provide the molecular basis for the clinically observed contiguous spread of the disease through the neuroaxis. In this review we examine the current state of knowledge regarding the prion-like properties of proteins associated with ALS pathology as well as their possible mechanisms of transmission.
    URL, DOI BibTeX

    @article{Grad2015,
    	abstract = "Prions, self-proliferating infectious agents consisting of misfolded protein, are most often associated with aggressive neurodegenerative diseases in animals and humans. Akin to the contiguous spread of a living pathogen, the prion paradigm provides a mechanism by which a mutant or wild-type misfolded protein can dominate pathogenesis through self-propagating protein misfolding, and subsequently spread from region to region through the central nervous system. The prion diseases, along with more common neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and the tauopathies belong to a larger group of protein misfolding disorders termed proteinopathies that feature aberrant misfolding and aggregation of specific proteins. Amyotrophic lateral sclerosis (ALS), a lethal disease characterized by progressive degeneration of motor neurons is currently understood as a classical proteinopathy; the disease is typified by the formation of inclusions consisting of aggregated protein within motor neurons that contribute to neurotoxicity. It is well established that misfolded/aggregated proteins such as SOD1 and TDP-43 contribute to the toxicity of motor neurons and play a prominent role in the pathology of ALS. Recent work has identified propagated protein misfolding properties in both mutant and wild-type SOD1, and to a lesser extent TDP-43, which may provide the molecular basis for the clinically observed contiguous spread of the disease through the neuroaxis. In this review we examine the current state of knowledge regarding the prion-like properties of proteins associated with ALS pathology as well as their possible mechanisms of transmission.",
    	author = "Grad, Leslie I and Fernando, Sarah M and Cashman, Neil R",
    	doi = "10.1016/j.nbd.2015.02.009",
    	issn = "1095-953X",
    	journal = "Neurobiology of disease",
    	month = "",
    	pages = "257--65",
    	pmid = 25701498,
    	title = "{From molecule to molecule and cell to cell: prion-like mechanisms in amyotrophic lateral sclerosis.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/25701498",
    	volume = 77,
    	year = 2015
    }
    
  4. Benjamin Wolozin.
    Physiological protein aggregation run amuck: stress granules and the genesis of neurodegenerative disease.. Discovery medicine 17(91):47–52, January 2014.
    Abstract Recent advances in neurodegenerative diseases point to novel mechanisms of protein aggregation. RNA binding proteins are abundant in the nucleus, where they carry out processes such as RNA splicing. Neurons also express RNA binding proteins in the cytoplasm and processes to enable functions such as mRNA transport and local protein synthesis. The biology of RNA binding proteins turns out to have important features that appear to promote the pathophysiology of amyotrophic lateral sclerosis and might contribute to other neurodegenerative disease. RNA binding proteins consolidate transcripts to form complexes, termed RNA granules, through a process of physiological aggregation mediated by glycine rich domains that exhibit low protein complexity and in some cases share homology to similar domains in known prion proteins. Under conditions of cell stress these RNA granules expand, leading to form stress granules, which function in part to sequester specialized transcript and promote translation of protective proteins. Studies in humans show that pathological aggregates occurring in ALS, Alzheimer's disease, and other dementias co-localize with stress granules. One increasingly appealing hypothesis is that mutations in RNA binding proteins or prolonged periods of stress cause formation of very stable, pathological stress granules. The consolidation of RNA binding proteins away from the nucleus and neuronal arbors into pathological stress granules might impair the normal physiological activities of these RNA binding proteins causing the neurodegeneration associated with these diseases. Conversely, therapeutic strategies focusing on reducing formation of pathological stress granules might be neuroprotective.
    URL BibTeX

    @article{Wolozin2014,
    	abstract = "Recent advances in neurodegenerative diseases point to novel mechanisms of protein aggregation. RNA binding proteins are abundant in the nucleus, where they carry out processes such as RNA splicing. Neurons also express RNA binding proteins in the cytoplasm and processes to enable functions such as mRNA transport and local protein synthesis. The biology of RNA binding proteins turns out to have important features that appear to promote the pathophysiology of amyotrophic lateral sclerosis and might contribute to other neurodegenerative disease. RNA binding proteins consolidate transcripts to form complexes, termed RNA granules, through a process of physiological aggregation mediated by glycine rich domains that exhibit low protein complexity and in some cases share homology to similar domains in known prion proteins. Under conditions of cell stress these RNA granules expand, leading to form stress granules, which function in part to sequester specialized transcript and promote translation of protective proteins. Studies in humans show that pathological aggregates occurring in ALS, Alzheimer's disease, and other dementias co-localize with stress granules. One increasingly appealing hypothesis is that mutations in RNA binding proteins or prolonged periods of stress cause formation of very stable, pathological stress granules. The consolidation of RNA binding proteins away from the nucleus and neuronal arbors into pathological stress granules might impair the normal physiological activities of these RNA binding proteins causing the neurodegeneration associated with these diseases. Conversely, therapeutic strategies focusing on reducing formation of pathological stress granules might be neuroprotective.",
    	author = "Wolozin, Benjamin",
    	issn = "1944-7930",
    	journal = "Discovery medicine",
    	month = "jan",
    	number = 91,
    	pages = "47--52",
    	pmid = 24411700,
    	title = "{Physiological protein aggregation run amuck: stress granules and the genesis of neurodegenerative disease.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/24411700",
    	volume = 17,
    	year = 2014
    }
    
  5. Keizo Sugaya and Imaharu Nakano.
    Prognostic role of “ prion-like propagation” in SOD1-linked familial ALS: an alternative view. Frontiers in Cellular Neuroscience 8:359, 2014.
    Abstract "Prion-like propagation" has recently been proposed for disease spread in Cu/Zn superoxide dismutase 1 (SOD1)-linked familial amyotrophic lateral sclerosis (ALS). Pathological SOD1 conformers are presumed to propagate via cell-to-cell transmission. In this model, the risk-based kinetics of neuronal cell loss over time appears to be represented by a sigmoidal function that reflects the kinetics of intercellular transmission. Here, we describe an alternative view of prion-like propagation in SOD1-linked ALS - its relation to disease prognosis under the protective-aggregation hypothesis. Nucleation-dependent polymerization has been widely accepted as the molecular mechanism of prion propagation. If toxic species of misfolded SOD1, as soluble oligomers, are formed as on-pathway intermediates of nucleation-dependent polymerization, further fibril extension via sequential addition of monomeric mutant SOD1 would be protective against neurodegeneration. This is because the concentration of unfolded mutant SOD1 monomers, which serve as precursor of nucleation and toxic species of mutant SOD1, would decline in proportion to the extent of aggregation. The nucleation process requires that native conformers exist in an unfolded state that may result from escaping the cellular protein quality control machinery. However, prion-like propagation-SOD1 aggregated form self-propagates by imposing its altered conformation on normal SOD1-appears to antagonize the protective role of aggregate growth. The cross-seeding reaction with normal SOD1 would lead to a failure to reduce the concentration of unfolded mutant SOD1 monomers, resulting in continuous nucleation and subsequent generation of toxic species, and influence disease prognosis. In this alternative view, the kinetics of neuronal loss appears to be represented by an exponential function, with decreasing risk reflecting the protective role of aggregate and the potential for cross-seeding reactions between mutant SOD1 and normal SOD1.
    URL, DOI BibTeX

    @article{Sugaya2014,
    	abstract = {"Prion-like propagation" has recently been proposed for disease spread in Cu/Zn superoxide dismutase 1 (SOD1)-linked familial amyotrophic lateral sclerosis (ALS). Pathological SOD1 conformers are presumed to propagate via cell-to-cell transmission. In this model, the risk-based kinetics of neuronal cell loss over time appears to be represented by a sigmoidal function that reflects the kinetics of intercellular transmission. Here, we describe an alternative view of prion-like propagation in SOD1-linked ALS - its relation to disease prognosis under the protective-aggregation hypothesis. Nucleation-dependent polymerization has been widely accepted as the molecular mechanism of prion propagation. If toxic species of misfolded SOD1, as soluble oligomers, are formed as on-pathway intermediates of nucleation-dependent polymerization, further fibril extension via sequential addition of monomeric mutant SOD1 would be protective against neurodegeneration. This is because the concentration of unfolded mutant SOD1 monomers, which serve as precursor of nucleation and toxic species of mutant SOD1, would decline in proportion to the extent of aggregation. The nucleation process requires that native conformers exist in an unfolded state that may result from escaping the cellular protein quality control machinery. However, prion-like propagation-SOD1 aggregated form self-propagates by imposing its altered conformation on normal SOD1-appears to antagonize the protective role of aggregate growth. The cross-seeding reaction with normal SOD1 would lead to a failure to reduce the concentration of unfolded mutant SOD1 monomers, resulting in continuous nucleation and subsequent generation of toxic species, and influence disease prognosis. In this alternative view, the kinetics of neuronal loss appears to be represented by an exponential function, with decreasing risk reflecting the protective role of aggregate and the potential for cross-seeding reactions between mutant SOD1 and normal SOD1.},
    	author = "Sugaya, Keizo and Nakano, Imaharu",
    	doi = "10.3389/fncel.2014.00359",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Sugaya, Nakano - 2014 - Prognostic role of \^{a}€\oe prion-like propagation\^{a}€ in SOD1-linked familial ALS an alternative view.pdf:pdf",
    	issn = "1662-5102",
    	journal = "Frontiers in Cellular Neuroscience",
    	month = "",
    	pages = 359,
    	pmid = 25400549,
    	title = "{Prognostic role of \^{a}€\oe prion-like propagation\^{a}€ in SOD1-linked familial ALS: an alternative view}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4215625\&tool=pmcentrez\&rendertype=abstract",
    	volume = 8,
    	year = 2014
    }
    
  6. Leslie I Grad, Edward Pokrishevsky, Judith M Silverman and Neil R Cashman.
    Exosome-dependent and independent mechanisms are involved in prion-like transmission of propagated Cu/Zn superoxide dismutase misfolding.. Prion 8(5):331–5, January 2014.
    Abstract Amyotrophic lateral sclerosis (ALS), a fatal adult-onset degenerative neuromuscular disorder with a poorly defined etiology, progresses in an orderly spatiotemporal manner from one or more foci within the nervous system, reminiscent of prion disease pathology. We have previously shown that misfolded mutant Cu/Zn superoxide dismutase (SOD1), mutation of which is associated with a subset of ALS cases, can induce endogenous wild-type SOD1 misfolding in the intracellular environment in a templating fashion similar to that of misfolded prion protein. Our recent observations further extend the prion paradigm of pathological SOD1 to help explain the intercellular transmission of disease along the neuroaxis. It has been shown that both mutant and misfolded wild-type SOD1 can traverse cell-to-cell either as protein aggregates that are released from dying cells and taken up by neighboring cells via macropinocytosis, or released to the extracellular environment on the surface of exosomes secreted from living cells. Furthermore, once propagation of misfolded wild-type SOD1 has been initiated in human cell culture, it continues over multiple passages of transfer and cell growth. Propagation and transmission of misfolded wild-type SOD1 is therefore a potential mechanism in the systematic progression of ALS pathology.
    URL, DOI BibTeX

    @article{Grad2014a,
    	abstract = "Amyotrophic lateral sclerosis (ALS), a fatal adult-onset degenerative neuromuscular disorder with a poorly defined etiology, progresses in an orderly spatiotemporal manner from one or more foci within the nervous system, reminiscent of prion disease pathology. We have previously shown that misfolded mutant Cu/Zn superoxide dismutase (SOD1), mutation of which is associated with a subset of ALS cases, can induce endogenous wild-type SOD1 misfolding in the intracellular environment in a templating fashion similar to that of misfolded prion protein. Our recent observations further extend the prion paradigm of pathological SOD1 to help explain the intercellular transmission of disease along the neuroaxis. It has been shown that both mutant and misfolded wild-type SOD1 can traverse cell-to-cell either as protein aggregates that are released from dying cells and taken up by neighboring cells via macropinocytosis, or released to the extracellular environment on the surface of exosomes secreted from living cells. Furthermore, once propagation of misfolded wild-type SOD1 has been initiated in human cell culture, it continues over multiple passages of transfer and cell growth. Propagation and transmission of misfolded wild-type SOD1 is therefore a potential mechanism in the systematic progression of ALS pathology.",
    	author = "Grad, Leslie I and Pokrishevsky, Edward and Silverman, Judith M and Cashman, Neil R",
    	doi = "10.4161/19336896.2014.983398",
    	issn = "1933-690X",
    	journal = "Prion",
    	month = "jan",
    	number = 5,
    	pages = "331--5",
    	pmid = 25551548,
    	title = "{Exosome-dependent and independent mechanisms are involved in prion-like transmission of propagated Cu/Zn superoxide dismutase misfolding.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/25551548",
    	volume = 8,
    	year = 2014
    }
    
  7. Leslie I Grad and Neil R Cashman.
    Prion-like activity of Cu/Zn superoxide dismutase: Implications for amyotrophic lateral sclerosis.. Prion 8(1), 2014.
    Abstract Neurodegenerative diseases belong to a larger group of protein misfolding disorders, known as proteinopathies. There is increasing experimental evidence implicating prion-like mechanisms in many common neurodegenerative disorders, including Alzheimer disease, Parkinson disease, the tauopathies, and amyotrophic lateral sclerosis (ALS), all of which feature the aberrant misfolding and aggregation of specific proteins. The prion paradigm provides a mechanism by which a mutant or wild-type protein can dominate pathogenesis through the initiation of self-propagating protein misfolding. ALS, a lethal disease characterized by progressive degeneration of motor neurons is understood as a classical proteinopathy; the disease is typified by the formation of inclusions consisting of aggregated protein within and around motor neurons that can contribute to neurotoxicity. It is well established that misfolded/oxidized SOD1 protein is highly toxic to motor neurons and plays a prominent role in the pathology of ALS. Recent work has identified propagated protein misfolding properties in both mutant and wild-type SOD1, which may provide the molecular basis for the clinically observed contiguous spread of the disease through the neuroaxis. In this review we examine the current state of knowledge regarding the prion-like properties of SOD1 and comment on its proposed mechanisms of intercellular transmission.
    URL BibTeX

    @article{Grad2014,
    	abstract = "Neurodegenerative diseases belong to a larger group of protein misfolding disorders, known as proteinopathies. There is increasing experimental evidence implicating prion-like mechanisms in many common neurodegenerative disorders, including Alzheimer disease, Parkinson disease, the tauopathies, and amyotrophic lateral sclerosis (ALS), all of which feature the aberrant misfolding and aggregation of specific proteins. The prion paradigm provides a mechanism by which a mutant or wild-type protein can dominate pathogenesis through the initiation of self-propagating protein misfolding. ALS, a lethal disease characterized by progressive degeneration of motor neurons is understood as a classical proteinopathy; the disease is typified by the formation of inclusions consisting of aggregated protein within and around motor neurons that can contribute to neurotoxicity. It is well established that misfolded/oxidized SOD1 protein is highly toxic to motor neurons and plays a prominent role in the pathology of ALS. Recent work has identified propagated protein misfolding properties in both mutant and wild-type SOD1, which may provide the molecular basis for the clinically observed contiguous spread of the disease through the neuroaxis. In this review we examine the current state of knowledge regarding the prion-like properties of SOD1 and comment on its proposed mechanisms of intercellular transmission.",
    	author = "Grad, Leslie I and Cashman, Neil R",
    	issn = "1933-690X",
    	journal = "Prion",
    	month = "",
    	number = 1,
    	pmid = 24394345,
    	title = "{Prion-like activity of Cu/Zn superoxide dismutase: Implications for amyotrophic lateral sclerosis.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/24394345",
    	volume = 8,
    	year = 2014
    }
    
  8. Jacob I Ayers, Susan Fromholt, Morgan Koch, Adam DeBosier, Ben McMahon, Guilian Xu and David R Borchelt.
    Experimental transmissibility of mutant SOD1 motor neuron disease. Acta Neuropathologica, 2014.
    Abstract By unknown mechanisms, the symptoms of amyotrophic lateral sclerosis (ALS) seem to spread along neuroanatomical pathways to engulf the motor nervous system. The rate at which symptoms spread is one of the primary drivers of disease progression. One mechanism by which ALS symptoms could spread is by a prion-like propagation of a toxic misfolded protein from cell to cell along neuroanatomic pathways. Proteins that can transmit toxic conformations between cells often can also experimentally transmit disease between individual organisms. To survey the ease with which motor neuron disease (MND) can be transmitted, we injected spinal cord homogenates prepared from paralyzed mice expressing mutant superoxide dismutase 1 (SOD1-G93A and G37R) into the spinal cords of genetically vulnerable SOD1 transgenic mice. From the various models we tested, one emerged as showing high vulnerability. Tissue homogenates from paralyzed G93A mice induced MND in 6 of 10 mice expressing low levels of G85R-SOD1 fused to yellow fluorescent protein (G85R-YFP mice) by 3-11 months, and produced widespread spinal inclusion pathology. Importantly, second passage of homogenates from G93A → G85R-YFP mice back into newborn G85R-YFP mice induced disease in 4 of 4 mice by 3 months of age. Homogenates from paralyzed mice expressing the G37R variant were among those that transmitted poorly regardless of the strain of recipient transgenic animal injected, a finding suggestive of strain-like properties that manifest as differing abilities to transmit MND. Together, our data provide a working model for MND transmission to study the pathogenesis of ALS.
    URL, DOI BibTeX

    @article{Ayers2014,
    	abstract = "By unknown mechanisms, the symptoms of amyotrophic lateral sclerosis (ALS) seem to spread along neuroanatomical pathways to engulf the motor nervous system. The rate at which symptoms spread is one of the primary drivers of disease progression. One mechanism by which ALS symptoms could spread is by a prion-like propagation of a toxic misfolded protein from cell to cell along neuroanatomic pathways. Proteins that can transmit toxic conformations between cells often can also experimentally transmit disease between individual organisms. To survey the ease with which motor neuron disease (MND) can be transmitted, we injected spinal cord homogenates prepared from paralyzed mice expressing mutant superoxide dismutase 1 (SOD1-G93A and G37R) into the spinal cords of genetically vulnerable SOD1 transgenic mice. From the various models we tested, one emerged as showing high vulnerability. Tissue homogenates from paralyzed G93A mice induced MND in 6 of 10 mice expressing low levels of G85R-SOD1 fused to yellow fluorescent protein (G85R-YFP mice) by 3-11 months, and produced widespread spinal inclusion pathology. Importantly, second passage of homogenates from G93A → G85R-YFP mice back into newborn G85R-YFP mice induced disease in 4 of 4 mice by 3 months of age. Homogenates from paralyzed mice expressing the G37R variant were among those that transmitted poorly regardless of the strain of recipient transgenic animal injected, a finding suggestive of strain-like properties that manifest as differing abilities to transmit MND. Together, our data provide a working model for MND transmission to study the pathogenesis of ALS.",
    	author = "Ayers, Jacob I. and Fromholt, Susan and Koch, Morgan and DeBosier, Adam and McMahon, Ben and Xu, Guilian and Borchelt, David R.",
    	doi = "10.1007/s00401-014-1342-7",
    	issn = "0001-6322",
    	journal = "Acta Neuropathologica",
    	month = "",
    	pmid = 25262000,
    	title = "{Experimental transmissibility of mutant SOD1 motor neuron disease}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/25262000",
    	year = 2014
    }
    
  9. Vinod Sundaramoorthy, Adam K Walker, Justin Yerbury, Kai Ying Soo, Manal A Farg, Vy Hoang, Rafaa Zeineddine, Damian Spencer and Julie D Atkin.
    Extracellular wildtype and mutant SOD1 induces ER-Golgi pathology characteristic of amyotrophic lateral sclerosis in neuronal cells.. Cellular and molecular life sciences : CMLS 70(21):4181–95, November 2013.
    Abstract Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing neurodegenerative disorder and the majority of ALS is sporadic, where misfolding and aggregation of Cu/Zn-superoxide dismutase (SOD1) is a feature shared with familial mutant-SOD1 cases. ALS is characterized by progressive neurospatial spread of pathology among motor neurons, and recently the transfer of extracellular, aggregated mutant SOD1 between cells was demonstrated in culture. However, there is currently no evidence that uptake of SOD1 into cells initiates neurodegenerative pathways reminiscent of ALS pathology. Similarly, whilst dysfunction to the ER-Golgi compartments is increasingly implicated in the pathogenesis of both sporadic and familial ALS, it remains unclear whether misfolded, wildtype SOD1 triggers ER-Golgi dysfunction. In this study we show that both extracellular, native wildtype and mutant SOD1 are taken up by macropinocytosis into neuronal cells. Hence uptake does not depend on SOD1 mutation or misfolding. We also demonstrate that purified mutant SOD1 added exogenously to neuronal cells inhibits protein transport between the ER-Golgi apparatus, leading to Golgi fragmentation, induction of ER stress and apoptotic cell death. Furthermore, we show that extracellular, aggregated, wildtype SOD1 also induces ER-Golgi pathology similar to mutant SOD1, leading to apoptotic cell death. Hence extracellular misfolded wildtype or mutant SOD1 induce dysfunction to ER-Golgi compartments characteristic of ALS in neuronal cells, implicating extracellular SOD1 in the spread of pathology among motor neurons in both sporadic and familial ALS.
    URL, DOI BibTeX

    @article{Sundaramoorthy2013,
    	abstract = "Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing neurodegenerative disorder and the majority of ALS is sporadic, where misfolding and aggregation of Cu/Zn-superoxide dismutase (SOD1) is a feature shared with familial mutant-SOD1 cases. ALS is characterized by progressive neurospatial spread of pathology among motor neurons, and recently the transfer of extracellular, aggregated mutant SOD1 between cells was demonstrated in culture. However, there is currently no evidence that uptake of SOD1 into cells initiates neurodegenerative pathways reminiscent of ALS pathology. Similarly, whilst dysfunction to the ER-Golgi compartments is increasingly implicated in the pathogenesis of both sporadic and familial ALS, it remains unclear whether misfolded, wildtype SOD1 triggers ER-Golgi dysfunction. In this study we show that both extracellular, native wildtype and mutant SOD1 are taken up by macropinocytosis into neuronal cells. Hence uptake does not depend on SOD1 mutation or misfolding. We also demonstrate that purified mutant SOD1 added exogenously to neuronal cells inhibits protein transport between the ER-Golgi apparatus, leading to Golgi fragmentation, induction of ER stress and apoptotic cell death. Furthermore, we show that extracellular, aggregated, wildtype SOD1 also induces ER-Golgi pathology similar to mutant SOD1, leading to apoptotic cell death. Hence extracellular misfolded wildtype or mutant SOD1 induce dysfunction to ER-Golgi compartments characteristic of ALS in neuronal cells, implicating extracellular SOD1 in the spread of pathology among motor neurons in both sporadic and familial ALS.",
    	author = "Sundaramoorthy, Vinod and Walker, Adam K and Yerbury, Justin and Soo, Kai Ying and Farg, Manal A and Hoang, Vy and Zeineddine, Rafaa and Spencer, Damian and Atkin, Julie D",
    	doi = "10.1007/s00018-013-1385-2",
    	issn = "1420-9071",
    	journal = "Cellular and molecular life sciences : CMLS",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: genetics,Amyotrophic Lateral Sclerosis: metabolism,Animals,Apoptosis,Cell Death,Cell Line,Endoplasmic Reticulum,Endoplasmic Reticulum: metabolism,Golgi Apparatus,Golgi Apparatus: metabolism,Humans,Immunohistochemistry,Mice,Motor Neurons,Motor Neurons: metabolism,Mutation,Neurons,Neurons: metabolism,Protein Folding,Superoxide Dismutase,Superoxide Dismutase: genetics,Superoxide Dismutase: metabolism",
    	month = "nov",
    	number = 21,
    	pages = "4181--95",
    	pmid = 23765103,
    	title = "{Extracellular wildtype and mutant SOD1 induces ER-Golgi pathology characteristic of amyotrophic lateral sclerosis in neuronal cells.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/23765103",
    	volume = 70,
    	year = 2013
    }
    
  10. Stanley B Prusiner.
    Biology and genetics of prions causing neurodegeneration.. Annual review of genetics 47:601–23, January 2013.
    Abstract Prions are proteins that acquire alternative conformations that become self-propagating. Transformation of proteins into prions is generally accompanied by an increase in $\beta$-sheet structure and a propensity to aggregate into oligomers. Some prions are beneficial and perform cellular functions, whereas others cause neurodegeneration. In mammals, more than a dozen proteins that become prions have been identified, and a similar number has been found in fungi. In both mammals and fungi, variations in the prion conformation encipher the biological properties of distinct prion strains. Increasing evidence argues that prions cause many neurodegenerative diseases (NDs), including Alzheimer's, Parkinson's, Creutzfeldt-Jakob, and Lou Gehrig's diseases, as well as the tauopathies. The majority of NDs are sporadic, and 10% to 20% are inherited. The late onset of heritable NDs, like their sporadic counterparts, may reflect the stochastic nature of prion formation; the pathogenesis of such illnesses seems to require prion accumulation to exceed some critical threshold before neurological dysfunction manifests.
    URL, DOI BibTeX

    @article{Prusiner2013,
    	abstract = "Prions are proteins that acquire alternative conformations that become self-propagating. Transformation of proteins into prions is generally accompanied by an increase in $\beta$-sheet structure and a propensity to aggregate into oligomers. Some prions are beneficial and perform cellular functions, whereas others cause neurodegeneration. In mammals, more than a dozen proteins that become prions have been identified, and a similar number has been found in fungi. In both mammals and fungi, variations in the prion conformation encipher the biological properties of distinct prion strains. Increasing evidence argues that prions cause many neurodegenerative diseases (NDs), including Alzheimer's, Parkinson's, Creutzfeldt-Jakob, and Lou Gehrig's diseases, as well as the tauopathies. The majority of NDs are sporadic, and 10\% to 20\% are inherited. The late onset of heritable NDs, like their sporadic counterparts, may reflect the stochastic nature of prion formation; the pathogenesis of such illnesses seems to require prion accumulation to exceed some critical threshold before neurological dysfunction manifests.",
    	author = "Prusiner, Stanley B",
    	doi = "10.1146/annurev-genet-110711-155524",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Prusiner - 2013 - Biology and genetics of prions causing neurodegeneration.pdf:pdf",
    	issn = "1545-2948",
    	journal = "Annual review of genetics",
    	keywords = "Age of Onset,Amyloidogenic Proteins,Amyloidogenic Proteins: chemistry,Amyloidogenic Proteins: classification,Amyloidogenic Proteins: physiology,Animals,Fungal Proteins,Fungal Proteins: chemistry,Fungal Proteins: classification,Fungal Proteins: physiology,Humans,Inclusion Bodies,Mammals,Models, Molecular,Neurodegenerative Diseases,Neurodegenerative Diseases: epidemiology,Neurodegenerative Diseases: etiology,Neurodegenerative Diseases: genetics,Neurofibrillary Tangles,Peptide Termination Factors,Peptide Termination Factors: chemistry,Peptide Termination Factors: classification,Peptide Termination Factors: physiology,Plaque, Amyloid,Prion Diseases,Prion Diseases: etiology,Prion Diseases: genetics,Prions,Prions: genetics,Prions: physiology,Protein Conformation,Saccharomyces cerevisiae Proteins,Saccharomyces cerevisiae Proteins: chemistry,Saccharomyces cerevisiae Proteins: classification,Saccharomyces cerevisiae Proteins: physiology,Synucleins,Synucleins: physiology,Tauopathies,Tauopathies: etiology,Tauopathies: genetics,Transcription Factors,Transcription Factors: chemistry,Transcription Factors: classification,Virulence,mRNA Cleavage and Polyadenylation Factors,mRNA Cleavage and Polyadenylation Factors: chemist,mRNA Cleavage and Polyadenylation Factors: classif,tau Proteins,tau Proteins: genetics,tau Proteins: physiology",
    	month = "jan",
    	pages = "601--23",
    	pmid = 24274755,
    	title = "{Biology and genetics of prions causing neurodegeneration.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4010318\&tool=pmcentrez\&rendertype=abstract",
    	volume = 47,
    	year = 2013
    }
    
  11. Kristen Marciniuk, Ryan Taschuk and Scott Napper.
    Evidence for prion-like mechanisms in several neurodegenerative diseases: potential implications for immunotherapy.. Clinical & developmental immunology 2013:473706, January 2013.
    Abstract Transmissible spongiform encephalopathies (TSEs) are fatal, untreatable neurodegenerative diseases. While the impact of TSEs on human health is relatively minor, these diseases are having a major influence on how we view, and potentially treat, other more common neurodegenerative disorders. Until recently, TSEs encapsulated a distinct category of neurodegenerative disorder, exclusive in their defining characteristic of infectivity. It now appears that similar mechanisms of self-propagation may underlie other proteinopathies such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, and Huntington's disease. This link is of scientific interest and potential therapeutic importance as this route of self-propagation offers conceptual support and guidance for vaccine development efforts. Specifically, the existence of a pathological, self-promoting isoform offers a rational vaccine target. Here, we review the evidence of prion-like mechanisms within a number of common neurodegenerative disorders and speculate on potential implications and opportunities for vaccine development.
    URL, DOI BibTeX

    @article{Marciniuk2013,
    	abstract = "Transmissible spongiform encephalopathies (TSEs) are fatal, untreatable neurodegenerative diseases. While the impact of TSEs on human health is relatively minor, these diseases are having a major influence on how we view, and potentially treat, other more common neurodegenerative disorders. Until recently, TSEs encapsulated a distinct category of neurodegenerative disorder, exclusive in their defining characteristic of infectivity. It now appears that similar mechanisms of self-propagation may underlie other proteinopathies such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, and Huntington's disease. This link is of scientific interest and potential therapeutic importance as this route of self-propagation offers conceptual support and guidance for vaccine development efforts. Specifically, the existence of a pathological, self-promoting isoform offers a rational vaccine target. Here, we review the evidence of prion-like mechanisms within a number of common neurodegenerative disorders and speculate on potential implications and opportunities for vaccine development.",
    	author = "Marciniuk, Kristen and Taschuk, Ryan and Napper, Scott",
    	doi = "10.1155/2013/473706",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Marciniuk, Taschuk, Napper - 2013 - Evidence for prion-like mechanisms in several neurodegenerative diseases potential implications for.pdf:pdf",
    	issn = "1740-2530",
    	journal = "Clinical \& developmental immunology",
    	keywords = "Animals,Epitopes,Epitopes: immunology,Humans,Immunotherapy,Models, Biological,Neurodegenerative Diseases,Neurodegenerative Diseases: diagnosis,Neurodegenerative Diseases: etiology,Neurodegenerative Diseases: therapy,PrPC Proteins,PrPC Proteins: immunology,PrPC Proteins: metabolism,PrPSc Proteins,PrPSc Proteins: immunology,PrPSc Proteins: metabolism,Prions,Prions: immunology,Prions: pathogenicity",
    	month = "jan",
    	pages = 473706,
    	pmid = 24228054,
    	title = "{Evidence for prion-like mechanisms in several neurodegenerative diseases: potential implications for immunotherapy.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3817797\&tool=pmcentrez\&rendertype=abstract",
    	volume = 2013,
    	year = 2013
    }
    
  12. Yun R Li, Oliver D King, James Shorter and Aaron D Gitler.
    Stress granules as crucibles of ALS pathogenesis.. The Journal of cell biology 201(3):361–72, 2013.
    Abstract Amyotrophic lateral sclerosis (ALS) is a fatal human neurodegenerative disease affecting primarily motor neurons. Two RNA-binding proteins, TDP-43 and FUS, aggregate in the degenerating motor neurons of ALS patients, and mutations in the genes encoding these proteins cause some forms of ALS. TDP-43 and FUS and several related RNA-binding proteins harbor aggregation-promoting prion-like domains that allow them to rapidly self-associate. This property is critical for the formation and dynamics of cellular ribonucleoprotein granules, the crucibles of RNA metabolism and homeostasis. Recent work connecting TDP-43 and FUS to stress granules has suggested how this cellular pathway, which involves protein aggregation as part of its normal function, might be coopted during disease pathogenesis.
    URL, DOI BibTeX

    @article{Li2013,
    	abstract = "Amyotrophic lateral sclerosis (ALS) is a fatal human neurodegenerative disease affecting primarily motor neurons. Two RNA-binding proteins, TDP-43 and FUS, aggregate in the degenerating motor neurons of ALS patients, and mutations in the genes encoding these proteins cause some forms of ALS. TDP-43 and FUS and several related RNA-binding proteins harbor aggregation-promoting prion-like domains that allow them to rapidly self-associate. This property is critical for the formation and dynamics of cellular ribonucleoprotein granules, the crucibles of RNA metabolism and homeostasis. Recent work connecting TDP-43 and FUS to stress granules has suggested how this cellular pathway, which involves protein aggregation as part of its normal function, might be coopted during disease pathogenesis.",
    	author = "Li, Yun R and King, Oliver D and Shorter, James and Gitler, Aaron D",
    	doi = "10.1083/jcb.201302044",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Li et al. - 2013 - Stress granules as crucibles of ALS pathogenesis.pdf:pdf",
    	issn = "1540-8140",
    	journal = "The Journal of cell biology",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: metabolism,Amyotrophic Lateral Sclerosis: pathology,Animals,Cytoplasmic Granules,Cytoplasmic Granules: metabolism,DNA-Binding Proteins,DNA-Binding Proteins: metabolism,Environmental Exposure,Humans,Nerve Tissue Proteins,Nerve Tissue Proteins: metabolism,Prions,Prions: metabolism,Protein Structure, Tertiary,RNA-Binding Protein FUS,RNA-Binding Protein FUS: metabolism,Stress, Physiological",
    	month = "",
    	number = 3,
    	pages = "361--72",
    	pmid = 23629963,
    	title = "{Stress granules as crucibles of ALS pathogenesis.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3639398\&tool=pmcentrez\&rendertype=abstract",
    	volume = 201,
    	year = 2013
    }
    
  13. Luigi Francesco Agnati, Diego Guidolin, Amina S Woods, Francisco Ciruela, Chiara Carone, Annamaria Vallelunga, Dasiel Oscar Borroto Escuela, Susanna Genedani and Kjell Fuxe.
    A new interpretative paradigm for Conformational Protein Diseases.. Current protein & peptide science 14(2):141–60, 2013.
    Abstract Conformational Protein Diseases (CPDs) comprise over forty clinically and pathologically diverse disorders in which specific altered proteins accumulate in cells or tissues of the body. The most studied are Alzheimer$\beta$'s disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, prion diseases, inclusion body myopathy, and the systemic amyloidoses. They are characterised by three dimensional conformational alterations, which are often rich in $\beta$- structure. Proteins in this non-native conformation are highly stable, resistant to degradation, and have an enhanced tendency to aggregate with like protein molecules. The misfolded proteins can impart their anomalous properties to soluble, monomeric proteins with the same amino acid sequence by a process that has been likened to seeded crystallization. However, these potentially pathogenic proteins also have important physiological actions, which have not completely characterized. This opens up the question of what process transforms physiological actions into pathological actions and most intriguing, is why potentially dangerous proteins have been maintained during evolution and are present from yeasts to humans. In the present paper, we introduce the concept of mis-exaptation and of mis-tinkering since they may help in clarifying some of the double edged sword aspects of these proteins. Against this background an original interpretative paradigm for CPDs will be given in the frame of the previously proposed Red Queen Theory of Aging.
    URL BibTeX

    @article{Agnati2013,
    	abstract = "Conformational Protein Diseases (CPDs) comprise over forty clinically and pathologically diverse disorders in which specific altered proteins accumulate in cells or tissues of the body. The most studied are Alzheimer$\beta$'s disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, prion diseases, inclusion body myopathy, and the systemic amyloidoses. They are characterised by three dimensional conformational alterations, which are often rich in $\beta$- structure. Proteins in this non-native conformation are highly stable, resistant to degradation, and have an enhanced tendency to aggregate with like protein molecules. The misfolded proteins can impart their anomalous properties to soluble, monomeric proteins with the same amino acid sequence by a process that has been likened to seeded crystallization. However, these potentially pathogenic proteins also have important physiological actions, which have not completely characterized. This opens up the question of what process transforms physiological actions into pathological actions and most intriguing, is why potentially dangerous proteins have been maintained during evolution and are present from yeasts to humans. In the present paper, we introduce the concept of mis-exaptation and of mis-tinkering since they may help in clarifying some of the double edged sword aspects of these proteins. Against this background an original interpretative paradigm for CPDs will be given in the frame of the previously proposed Red Queen Theory of Aging.",
    	author = "Agnati, Luigi Francesco and Guidolin, Diego and Woods, Amina S and Ciruela, Francisco and Carone, Chiara and Vallelunga, Annamaria and Escuela, Dasiel Oscar Borroto and Genedani, Susanna and Fuxe, Kjell",
    	issn = "1875-5550",
    	journal = "Current protein \& peptide science",
    	keywords = "Aging,Aging: metabolism,Alzheimer Disease,Alzheimer Disease: metabolism,Humans,Parkinson Disease,Parkinson Disease: metabolism,Prion Diseases,Prion Diseases: metabolism,Protein Conformation,Protein Folding,Proteins,Proteins: chemistry,Proteins: metabolism",
    	month = "",
    	number = 2,
    	pages = "141--60",
    	pmid = 23441893,
    	title = "{A new interpretative paradigm for Conformational Protein Diseases.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/23441893",
    	volume = 14,
    	year = 2013
    }
    
  14. Kunihiro Yoshida, Keiichi Higuchi and Shu-ichi Ikeda.
    [Can prion-like propagation occur in neurodegenerative diseases?: in view of transmissible systemic amyloidosis].. Brain and nerve = Shinkei kenkyū no shinpo 64(6):665–74, 2012.
    Abstract Common neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are now considered as "protein misfolding diseases," because the misfolding of a small number of proteins is a key event in the pathogenesis and progression of these diseases. Proteins that are prone to misfolding and thereby associated with neurodegenerative diseases include amyloid $\beta$ (AD), tau (AD and tauopathy), $\alpha$-synuclein (PD, dementia with Lewy bodies, etc.), polyglutamine proteins (Huntington's disease, spinocerebellar ataxia, etc.), and superoxide dismutase 1 (amyotrophic lateral sclerosis). These proteins share certain essential properties with prions. Similar to abnormal prions, misfolded proteins function as a template to catalyze the misfolding of the native proteins and assemble into insoluble, $\beta$-sheet-rich, fibrillar aggregates termed as "amyloids." Furthermore, there is enough evidence supporting the intercellular transfer of misfolded protein aggregates. The transmission of these aggregates from one cell to another may be in accordance with the concept that neuropathological changes propagate along neuronal circuits in neurodegenerative diseases. Prion-like propagation mechanisms have been extensively analyzed in connection with systemic amyloidoses such as amyloid A (AA) amyloidosis and amyloid apolipoprotein AII (AApoAII) amyloidosis. Studies have shown that AA and AApoAII amyloidoses are transmitted from one organism to another through amyloid fibrils. However, studies have not yet proved that protein misfolding diseases, except for prion diseases, are infectious. Given the intercellular transfer of misfolded protein aggregates, we cannot ignore the possibility that disease-specific, misfolded proteins can be transmitted between individuals through surgical procedures or tissue transplantation. Importantly, cell non-autonomous mechanisms underlying the pathogenesis of neurodegenerative diseases may represent a more readily accessible target for novel disease-modifying therapies. In the present review, we discuss some aspects of the prion-like propagation of neurodegenerative diseases, taking into consideration the accumulated evidence supporting the transmissibility of systemic amyloidoses.
    URL BibTeX

    @article{Yoshida2012,
    	abstract = {Common neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are now considered as "protein misfolding diseases," because the misfolding of a small number of proteins is a key event in the pathogenesis and progression of these diseases. Proteins that are prone to misfolding and thereby associated with neurodegenerative diseases include amyloid $\beta$ (AD), tau (AD and tauopathy), $\alpha$-synuclein (PD, dementia with Lewy bodies, etc.), polyglutamine proteins (Huntington's disease, spinocerebellar ataxia, etc.), and superoxide dismutase 1 (amyotrophic lateral sclerosis). These proteins share certain essential properties with prions. Similar to abnormal prions, misfolded proteins function as a template to catalyze the misfolding of the native proteins and assemble into insoluble, $\beta$-sheet-rich, fibrillar aggregates termed as "amyloids." Furthermore, there is enough evidence supporting the intercellular transfer of misfolded protein aggregates. The transmission of these aggregates from one cell to another may be in accordance with the concept that neuropathological changes propagate along neuronal circuits in neurodegenerative diseases. Prion-like propagation mechanisms have been extensively analyzed in connection with systemic amyloidoses such as amyloid A (AA) amyloidosis and amyloid apolipoprotein AII (AApoAII) amyloidosis. Studies have shown that AA and AApoAII amyloidoses are transmitted from one organism to another through amyloid fibrils. However, studies have not yet proved that protein misfolding diseases, except for prion diseases, are infectious. Given the intercellular transfer of misfolded protein aggregates, we cannot ignore the possibility that disease-specific, misfolded proteins can be transmitted between individuals through surgical procedures or tissue transplantation. Importantly, cell non-autonomous mechanisms underlying the pathogenesis of neurodegenerative diseases may represent a more readily accessible target for novel disease-modifying therapies. In the present review, we discuss some aspects of the prion-like propagation of neurodegenerative diseases, taking into consideration the accumulated evidence supporting the transmissibility of systemic amyloidoses.},
    	author = "Yoshida, Kunihiro and Higuchi, Keiichi and Ikeda, Shu-ichi",
    	issn = "1881-6096",
    	journal = "Brain and nerve = Shinkei kenkyū no shinpo",
    	keywords = "Amyloidosis,Amyloidosis: metabolism,Amyloidosis: therapy,Animals,Humans,Neurodegenerative Diseases,Neurodegenerative Diseases: metabolism,Neurodegenerative Diseases: therapy,Prions,Prions: metabolism,Protein Folding,Signal Transduction",
    	month = "",
    	number = 6,
    	pages = "665--74",
    	pmid = 22647474,
    	title = "{[Can prion-like propagation occur in neurodegenerative diseases?: in view of transmissible systemic amyloidosis].}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/22647474",
    	volume = 64,
    	year = 2012
    }
    
  15. Robert H Baloh.
    How do the RNA-binding proteins TDP-43 and FUS relate to amyotrophic lateral sclerosis and frontotemporal degeneration, and to each other?. Current opinion in neurology 25(6):701–7, 2012.
    Abstract PURPOSE OF REVIEW: This review examines the recent research developments aimed at defining the role of RNA-binding proteins (TDP-43 and FUS) in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). RECENT FINDINGS: TAR DNA-binding protein 43 kDa (TDP-43) and fused in sarcoma (FUS) are RNA-binding proteins that form aggregates in ALS and FTLD, and when mutated can drive the pathogenesis of these disorders. However, fundamental questions remain as to the relationship between TDP-43 and FUS aggregation and disease, their normal and pathologic function, and where they converge on the same cellular pathways. Autopsy series point to distinct molecular actions as TDP-43 and FUS neuronal inclusions do not overlap, with FUS inclusions being present in only a small subgroup of patients. By contrast, modeling experiments in lower organisms support a genetic interaction between TDP-43 and FUS, although it is likely indirect. Regardless, the recent finding that additional RNA-binding proteins may also cause ALS, and the observation that TDP-43 aggregation remains a core feature in all of the recently identified genetic forms of ALS (C9ORF72, VCP, UBQLN2, and PFN1), underscores the central role of TDP-43 and RNA metabolism in ALS and FTLD. SUMMARY: Recent discoveries point to an unprecedented convergence of molecular pathways in ALS and FTLD involving RNA metabolism. Defining the exact points of convergence will likely be key to advancing therapeutics development in the coming years.
    URL, DOI BibTeX

    @article{Baloh2012,
    	abstract = "PURPOSE OF REVIEW: This review examines the recent research developments aimed at defining the role of RNA-binding proteins (TDP-43 and FUS) in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). RECENT FINDINGS: TAR DNA-binding protein 43 kDa (TDP-43) and fused in sarcoma (FUS) are RNA-binding proteins that form aggregates in ALS and FTLD, and when mutated can drive the pathogenesis of these disorders. However, fundamental questions remain as to the relationship between TDP-43 and FUS aggregation and disease, their normal and pathologic function, and where they converge on the same cellular pathways. Autopsy series point to distinct molecular actions as TDP-43 and FUS neuronal inclusions do not overlap, with FUS inclusions being present in only a small subgroup of patients. By contrast, modeling experiments in lower organisms support a genetic interaction between TDP-43 and FUS, although it is likely indirect. Regardless, the recent finding that additional RNA-binding proteins may also cause ALS, and the observation that TDP-43 aggregation remains a core feature in all of the recently identified genetic forms of ALS (C9ORF72, VCP, UBQLN2, and PFN1), underscores the central role of TDP-43 and RNA metabolism in ALS and FTLD. SUMMARY: Recent discoveries point to an unprecedented convergence of molecular pathways in ALS and FTLD involving RNA metabolism. Defining the exact points of convergence will likely be key to advancing therapeutics development in the coming years.",
    	author = "Baloh, Robert H",
    	doi = "10.1097/WCO.0b013e32835a269b",
    	issn = "1473-6551",
    	journal = "Current opinion in neurology",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: genetics,Amyotrophic Lateral Sclerosis: metabolism,DNA-Binding Proteins,DNA-Binding Proteins: genetics,DNA-Binding Proteins: metabolism,Frontotemporal Lobar Degeneration,Frontotemporal Lobar Degeneration: genetics,Frontotemporal Lobar Degeneration: metabolism,Humans,RNA,RNA-Binding Protein FUS,RNA-Binding Protein FUS: genetics,RNA-Binding Protein FUS: metabolism,RNA: metabolism",
    	month = "",
    	number = 6,
    	pages = "701--7",
    	pmid = 23041957,
    	title = "{How do the RNA-binding proteins TDP-43 and FUS relate to amyotrophic lateral sclerosis and frontotemporal degeneration, and to each other?}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/23041957",
    	volume = 25,
    	year = 2012
    }
    
  16. Marka Blitterswijk, Sunita Gulati, Elizabeth Smoot, Matthew Jaffa, Nancy Maher, Bradley T Hyman, Adrian J Ivinson, Clemens R Scherzer, David A Schoenfeld, Merit E Cudkowicz, Robert H Brown and Daryl A Bosco.
    Anti-superoxide dismutase antibodies are associated with survival in patients with sporadic amyotrophic lateral sclerosis.. Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases 12(6):430–8, 2011.
    Abstract Our objective was to test the hypothesis that aberrantly modified forms of superoxide dismutase (SOD1) influence the disease course for sporadic amyotrophic lateral sclerosis (SALS). We probed for anti-SOD1 antibodies (IgM and IgG) against both the normal and aberrantly oxidized-SOD1 (SODox) antigens in sera from patients with SALS, subjects diagnosed with other neurological disorders and healthy individuals, and correlated the levels of these antibodies to disease duration and/or severity. Anti-SOD1 antibodies were detected in all cohorts; however, a subset of ∼5-10% of SALS cases exhibited elevated levels of anti-SOD1 antibodies. Those SALS cases with relatively high levels of IgM antibodies against SODox exhibit a longer survival of 6.4 years, compared to subjects lacking these antibodies. By contrast, SALS subjects expressing higher levels of IgG antibodies reactive for the normal WT-SOD1 antigen exhibit a shorter survival of 4.1 years. Anti-SOD1 antibody levels did not correlate with disease severity in either the Alzheimer's or Parkinson's disease cohorts. In conclusion, the association of longer survival with elevated levels of anti-SODox antibodies suggests that these antibodies may be protective. By extension, these data implicate aberrantly modified forms of WT-SOD1 (e.g. oxidized SOD1) in SALS pathogenesis. In contrast, an immune response against the normal WT-SOD1 appears to be disadvantageous in SALS, possibly because the anti-oxidizing activity of normal WT-SOD1 is beneficial to SALS individuals.
    URL, DOI BibTeX

    @article{VanBlitterswijk2011,
    	abstract = "Our objective was to test the hypothesis that aberrantly modified forms of superoxide dismutase (SOD1) influence the disease course for sporadic amyotrophic lateral sclerosis (SALS). We probed for anti-SOD1 antibodies (IgM and IgG) against both the normal and aberrantly oxidized-SOD1 (SODox) antigens in sera from patients with SALS, subjects diagnosed with other neurological disorders and healthy individuals, and correlated the levels of these antibodies to disease duration and/or severity. Anti-SOD1 antibodies were detected in all cohorts; however, a subset of ∼5-10\% of SALS cases exhibited elevated levels of anti-SOD1 antibodies. Those SALS cases with relatively high levels of IgM antibodies against SODox exhibit a longer survival of 6.4 years, compared to subjects lacking these antibodies. By contrast, SALS subjects expressing higher levels of IgG antibodies reactive for the normal WT-SOD1 antigen exhibit a shorter survival of 4.1 years. Anti-SOD1 antibody levels did not correlate with disease severity in either the Alzheimer's or Parkinson's disease cohorts. In conclusion, the association of longer survival with elevated levels of anti-SODox antibodies suggests that these antibodies may be protective. By extension, these data implicate aberrantly modified forms of WT-SOD1 (e.g. oxidized SOD1) in SALS pathogenesis. In contrast, an immune response against the normal WT-SOD1 appears to be disadvantageous in SALS, possibly because the anti-oxidizing activity of normal WT-SOD1 is beneficial to SALS individuals.",
    	author = "van Blitterswijk, Marka and Gulati, Sunita and Smoot, Elizabeth and Jaffa, Matthew and Maher, Nancy and Hyman, Bradley T and Ivinson, Adrian J and Scherzer, Clemens R and Schoenfeld, David A and Cudkowicz, Merit E and Brown, Robert H and Bosco, Daryl A",
    	doi = "10.3109/17482968.2011.585163",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/van Blitterswijk et al. - 2011 - Anti-superoxide dismutase antibodies are associated with survival in patients with sporadic amyotrophic.pdf:pdf",
    	issn = "1471-180X",
    	journal = "Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases",
    	keywords = "Adult,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: blood,Amyotrophic Lateral Sclerosis: immunology,Amyotrophic Lateral Sclerosis: mortality,Animals,Autoantibodies,Autoantibodies: blood,Autoantibodies: immunology,Female,Humans,Male,Middle Aged,Superoxide Dismutase,Superoxide Dismutase: immunology,Survival",
    	month = "",
    	number = 6,
    	pages = "430--8",
    	pmid = 22023190,
    	title = "{Anti-superoxide dismutase antibodies are associated with survival in patients with sporadic amyotrophic lateral sclerosis.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3446817\&tool=pmcentrez\&rendertype=abstract",
    	volume = 12,
    	year = 2011
    }
    
  17. Ashok Verma.
    Protein aggregates and regional disease spread in ALS is reminiscent of prion-like pathogenesis.. Neurology India 61(2):107–10.
    Abstract Amyotrophic lateral sclerosis (ALS) typically commences in a discrete location in a limb or bulbar territory muscles and then spreads to the adjacent anatomical regions. This pattern is consistent with a contiguous spread of the disease process in motor neuron network resulting in progressive motor weakness. The etiology of ALS onset and the mechanism of the regional ALS spread remain elusive. Over the past 5 years, identification of mutations in two RNA binding proteins, trans active response (TAR) DNA-binding protein (TDP-43) and fused in sarcoma (FUS), in patients with familial ALS has led to a major shift in our understanding of the ALS disease mechanism. In addition to their role in RNA metabolism, TDP-43 and FUS form protein aggregates in the affected neurons. More recent findings demonstrating that both TDP-43 and FUS contain glutamine/asparagine (Q/N) residue-rich prion-like domains have spurred intense research interest. This brief review discusses the prion-related domains in TDP-43 and FUS and their implication in protein aggregate formation and disease spread in ALS.
    URL, DOI BibTeX

    @article{Verma,
    	abstract = "Amyotrophic lateral sclerosis (ALS) typically commences in a discrete location in a limb or bulbar territory muscles and then spreads to the adjacent anatomical regions. This pattern is consistent with a contiguous spread of the disease process in motor neuron network resulting in progressive motor weakness. The etiology of ALS onset and the mechanism of the regional ALS spread remain elusive. Over the past 5 years, identification of mutations in two RNA binding proteins, trans active response (TAR) DNA-binding protein (TDP-43) and fused in sarcoma (FUS), in patients with familial ALS has led to a major shift in our understanding of the ALS disease mechanism. In addition to their role in RNA metabolism, TDP-43 and FUS form protein aggregates in the affected neurons. More recent findings demonstrating that both TDP-43 and FUS contain glutamine/asparagine (Q/N) residue-rich prion-like domains have spurred intense research interest. This brief review discusses the prion-related domains in TDP-43 and FUS and their implication in protein aggregate formation and disease spread in ALS.",
    	author = "Verma, Ashok",
    	doi = "10.4103/0028-3886.111109",
    	issn = "0028-3886",
    	journal = "Neurology India",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: genetics,Amyotrophic Lateral Sclerosis: metabolism,Amyotrophic Lateral Sclerosis: pathology,Brain,Brain: metabolism,Brain: pathology,DNA-Binding Proteins,DNA-Binding Proteins: genetics,DNA-Binding Proteins: metabolism,Humans,Prions,Prions: genetics,Prions: metabolism,RNA-Binding Protein FUS,RNA-Binding Protein FUS: genetics,RNA-Binding Protein FUS: metabolism",
    	number = 2,
    	pages = "107--10",
    	pmid = 23644307,
    	title = "{Protein aggregates and regional disease spread in ALS is reminiscent of prion-like pathogenesis.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/23644307",
    	volume = 61
    }
    

 

Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and -independent mechanisms

http://www.phas.ubc.ca/~steve/publication/GradCashman_PNAS14.pdf

Jan 28, 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.

 

Cell-to-cell transmission of pathogenic proteins in neurodegenerative diseases

Feb 6, 2014

http://www.nature.com/nm/journal/v20/n2/abs/nm.3457.html

Abstract

 common feature of many neurodegenerative diseases is the deposition of β-sheet-rich amyloid aggregates formed by proteins specific to these diseases. These protein aggregates are thought to cause neuronal dysfunction, directly or indirectly. Recent studies have strongly implicated cell-to-cell transmission of misfolded proteins as a common mechanism for the onset and progression of various neurodegenerative disorders. Emerging evidence also suggests the presence of conformationally diverse 'strains' of each type of disease protein, which may be another shared feature of amyloid aggregates, accounting for the tremendous heterogeneity within each type of neurodegenerative disease. Although there are many more questions to be answered, these studies have opened up new avenues for therapeutic interventions in neurodegenerative disorders.

 

About the prion-like misfolding of TDP-43

http://www.uphs.upenn.edu/news/publications/PENNMedicine/files/pm-spring2012-saga-disease-protein.pdf