Aggregate formation in the spinal cord of mutant SOD1 transgenic mice is reversible and mediated by proteasomes

Puttaparthi, Krishna; Wojcik, Cezary; Rajendran, Bhagya; DeMartino, George N.; Elliott, Jeffrey L.

doi:10.1046/j.1471-4159.2003.02028.x

Cited by 64 publications

(45 citation statements)

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“…That these aggregates are central to the pathogenesis of disease forms the basis for the aggregation or protein mishandling model of ALS (Kabashi and Durham, 2006). Much experimental evidence has found that mutant SOD1 and its aggregates are cleared by proteasome mediated degradation pathways raising the possibility that alterations in proteasome function in vivo might influence the rate of aggregate accumulation and change disease course (Johnston et al, 2000;Puttaparthi et al, 2003;Di Noto et al, 2005). Several groups have found that there is induction of immuno-proteasomes in the spinal cords of mutant SOD1 transgenic mice as they develop neurological dysfunction suggesting a potential compensatory role for immuno-proteasomes as a response to the increasing accumulation of SOD1 aggregates (Cheroni et al, 2005;Puttaparthi and Elliott, 2005;Ahtoniemi et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Puttaparthi et al, 2003;Di Noto et al, 2005). Early in vitro work with protein aggregates had predicted that proteasome function might be inhibited in neurodegenerative diseases, but studies using transgenic rodent models of Huntington's disease and ALS found that instead there appeared to be induction of proteasome activity within the CNS as the animals developed neurological disease (Bence et al, 2001;Diaz-Hernandez et al, 2003;Kabashi et al, 2004;Cheroni et al, 2005;Puttaparthi and Elliott, 2005;Ahtoniemi et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Assessing the role of immuno-proteasomes in a mouse model of familial ALS

Puttaparthi

Kaer

Elliott

2007

Experimental Neurology

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The accumulation of protein aggregates is thought to be an important component in the pathogenesis of mutant SOD1 induced disease. Mutant SOD1 aggregates appear to be cleared by proteasomes, at least in vitro, suggesting a potentially important role for proteasome degradation pathways in vivo. G93A SOD1 transgenic mice show an increase in proteasome activity and induction of immunoproteasome subunits within spinal cord as they develop neurological symptoms. To determine what role immuno-proteasomes may have in mutant SOD1 induced disease, we crossed G93A SOD1 transgenic mice with LMP2−/− mice to obtain G93A SOD1 mice lacking the LMP2 immunoproteasome subunit. G93A SOD1/LMP2−/− mice show significant reductions in proteasome function within spinal cord compared to G93A SOD1 mice. However, G93A SOD1/LMP2−/− mice show no change in motor function decline, or survival compared to G93A SOD1 mice. These results indicate that the loss of immuno-proteasome function in vivo does not significantly alter mutant SOD1 induced disease. Keywords ALS; motor neuron; spinal cord; astrocyte; microglia; aggregation Mutations in the gene encoding Cu, Zn superoxide dismutase (SOD1) cause one form of familial amyotrophic lateral sclerosis (FALS) linked to chromosome 21q (Rosen et al., 1993). Studies using SOD1 knockout or transgenic mice expressing mutant SOD1 have established a toxic gain of function model for the abnormal SOD1 protein that may be related to protein misfolding and aggregation (Gurney et al., 1994;Ripps et al., 1995;Wong et al., 1995;Reaume et al., 1996;Kabashi and Durham, 2006). Indeed, the presence of SOD1 positive aggregates is a pathologic hallmark of disease both in transgenic mutant SOD1 mice and in patients dying from SOD1 related FALS (Shibata et al., 1996;Watanabe et al., 2001). SOD1 aggregates accumulate as the disease progresses and can be visualized as high molecular weight protein complexes (HMWPCs) on Western gels or as ubiquitin positive cellular inclusions via immuno-staining (Bruijn et al., 1997;Johnston et al., 2000;Wang et al., 2002). The finding Correspondence to: Jeffrey L. Elliott. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Puttaparthi et al., 2003;Di Noto et al., 2005). Early in vitro work with protein aggregates had predicted that proteasome function might be inhibited in neurodegenerative diseases, but studies using transgenic rodent models of Huntington's disease and ALS found that instead there appeared to be induction of proteasome activity within the CNS as the animals developed neurological disease (Bence et al., 2001;Diaz-Hernandez et ...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Assessing the role of immuno-proteasomes in a mouse model of familial ALS

Puttaparthi

Kaer

Elliott

2007

Experimental Neurology

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“…Mutant SOD1 may cause excitotoxicity in motor neurons by inducing mitochondrial dysfunction and impairing glial glutamate transporter function (45,46). Additionally, mutant SOD1 causes disorganization of the cytoskeleton and disrupts axonal transport (47,48), compromises proteasome activity (37,49), (which in turn causes accumulation and aggregation of mutant SOD1 (35,50)), and induces inflammation (51-54) (which may accelerate the disease progression (55)(56)(57)). These downstream effects of mutant SOD1 presumably trigger the final programmed cell death in motor neurons (58).…”

Section: Amyotrophic Lateral Sclerosis (Als)mentioning

confidence: 99%

Inhibition of Chaperone Activity Is a Shared Property of Several Cu,Zn-Superoxide Dismutase Mutants That Cause Amyotrophic Lateral Sclerosis

Tummala

Jung

Tiwari

et al. 2005

Journal of Biological Chemistry

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron degeneration, paralysis, and death. Mutant Cu,Znsuperoxide dismutase (SOD1) causes a subset of ALS by an unidentified toxic property. Increasing evidence suggests that chaperone dysfunction plays a role in motor neuron degeneration in ALS. To investigate the relationship between mutant SOD1 expression and chaperone dysfunction, we measured chaperone function in central nervous system tissue lysates from normal mice and transgenic mice expressing human SOD1 variants. We observed a significant decrease in chaperone activity in tissues from mice expressing ALS-linked mutant SOD1 but not control mice expressing human wild type SOD1. This decrease was detected only in the spinal cord, became apparent by 60 days of age (before the onset of muscle weakness and significant motor neuron loss), and persisted throughout the late stages. In addition, this impairment of chaperone activity occurred only in cytosolic but not in mitochondrial and nuclear fractions. Furthermore, multiple recombinant human SOD1 mutants with differing biochemical and biophysical properties inhibited chaperone function in a cell-free extract of normal mouse spinal cords. Thus, mutant SOD1 proteins may impair chaperone function independent of gene expression in vivo, and this inhibition may be a shared property of ALS-linked mutant SOD1 proteins.

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“…Ten percent of ALS cases are familial (fALS), with 20% of fALS being linked to mutations in the homodimeric protein Cu/Zn superoxide dismutase 1 (SOD1) (6-8). In animal models and in humans carrying SOD1 mutations, mutant SOD1 is "toxic" only to motor neurons, and only after it has been present for an extended period (aging), leading to the important questions of how mutant SOD1 exerts its toxicity and why motor neurons are particularly sensitive to the pathogenic process.Mutant SOD1 has a high propensity to undergo conformational changes and aggregation when stressed in vitro, and SOD1 aggregates and misfolded aggregate precursors have been localized specifically to pathologically affected tissues in animal models of disease, suggesting that SOD1 conformational changes may contribute to the toxicity of the mutant protein (9)(10)(11)(12)(13)(14). It has been further demonstrated that conformational changes in wildtype SOD1 can be induced through oxidation and/or metal depletion and that these conformers of the wild-type protein are also toxic in cellular models (15-18).…”

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confidence: 99%

Localization of a toxic form of superoxide dismutase 1 protein to pathologically affected tissues in familial ALS

Brotherton

Cooper

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in the gene encoding superoxide dismutase 1 (SOD1) account for about 20% of the cases of familial amyotrophic lateral sclerosis (fALS). It is not known how the mutant protein causes disease, or why only a subset of cell types (motor neurons) are targeted. The aggregation and misfolding of mutant SOD1 are implicated in disease pathogenesis in both animal models and humans. We used a monoclonal antibody, C4F6, which specifically reacts with mutant and/or "misfolded" SOD1, to investigate the regional distribution of mutant SOD1 protein in rodent and human tissues. C4F6 reacted only with mutant SOD1 and showed remarkable selectivity for disease-affected tissues and cells. Tissue not affected by disease but containing high levels of mutant protein (sensory neurons) did not stain with C4F6. Additionally, C4F6 intensely stained some motor neurons while leaving adjacent motor neurons unstained. Although C4F6 was generated against the G93A SOD1 mutant, it also recognized other SOD1 mutants. In human autopsy tissues from patients carrying SOD1 mutations, C4F6 identified skein-like intracellular inclusions in motor neurons, similar to those seen in rodents, and again stained only a subset of motor neurons. In spinal cords from patients with sporadic ALS, other neurodegenerative diseases, and normal controls, C4F6-immunoreactive inclusions were not detected, but the antibody did reveal diffuse immunostaining of some spinal motor neurons. The ability of C4F6 to differentiate pathologically affected tissue in mutant SOD1 ALS rodent models and humans, specifically motor neuron populations, suggests that this antibody may recognize a "toxic" form of the mutant SOD1 protein.aggregate | misfold | soluble A myotrophic lateral sclerosis (ALS) is a progressive, adultonset motor neuron disease with an incidence of one to two persons per 100,000 (1, 2). ALS typically causes death within 3-5 y of diagnosis; there is no cure and treatment options are very limited (3-5). Ten percent of ALS cases are familial (fALS), with 20% of fALS being linked to mutations in the homodimeric protein Cu/Zn superoxide dismutase 1 (SOD1) (6-8). In animal models and in humans carrying SOD1 mutations, mutant SOD1 is "toxic" only to motor neurons, and only after it has been present for an extended period (aging), leading to the important questions of how mutant SOD1 exerts its toxicity and why motor neurons are particularly sensitive to the pathogenic process.Mutant SOD1 has a high propensity to undergo conformational changes and aggregation when stressed in vitro, and SOD1 aggregates and misfolded aggregate precursors have been localized specifically to pathologically affected tissues in animal models of disease, suggesting that SOD1 conformational changes may contribute to the toxicity of the mutant protein (9)(10)(11)(12)(13)(14). It has been further demonstrated that conformational changes in wildtype SOD1 can be induced through oxidation and/or metal depletion and that these conformers of the wild-type protein are also toxic in cellular models...

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Aggregate formation in the spinal cord of mutant SOD1 transgenic mice is reversible and mediated by proteasomes

Cited by 64 publications

References 31 publications

Assessing the role of immuno-proteasomes in a mouse model of familial ALS

Assessing the role of immuno-proteasomes in a mouse model of familial ALS

Inhibition of Chaperone Activity Is a Shared Property of Several Cu,Zn-Superoxide Dismutase Mutants That Cause Amyotrophic Lateral Sclerosis

Localization of a toxic form of superoxide dismutase 1 protein to pathologically affected tissues in familial ALS

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