Advanced glycation endproduct-modified superoxide dismutase-1 (SOD1)-positive inclusions are common to familial amyotrophic lateral sclerosis patients with SOD1 gene mutations and transgenic mice expressing human SOD1 with a G85R mutation

Kato, Shinsuke; Horiuchi, Shinya; Liu, Jian; Cleveland, Don W.; Shibata, Noriyuki; Nakashima, Kenichiro; Nagai, Ryoji; Hirano, Atsushi; Takikawa, Miki; Kato, Masako; Nakano, Imaharu; Ohama, Eisaku

doi:10.1007/s004010000226

Cited by 67 publications

(38 citation statements)

References 77 publications

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“…Both total and specific activities of the proteasome were reduced to a similar extent, indicating that a change in proteasome function, rather than a decrease in proteasome levels, had occurred. Similar decreases of total and specific activities of the proteasome were observed in NIH 3T3 cell lines expressing fALS mutants SOD-1 G93A and SOD- Wang et al 2002), and patients with sporadic or fALS (Shibata et al 1996;Kato et al 2000). Proteinaceous inclusions are a common feature of several neurodegenerative disorders and their occurrence suggests an overload of protein chaperones and ubiquitin-proteasome pathways, which sequester, refold or degrade abnormal proteins (Kopito 2000;McNaught et al 2001;Sherman and Goldberg 2001;Ciechanover and Brundin 2003).…”

Section: Introductionmentioning

confidence: 68%

Focal dysfunction of the proteasome: a pathogenic factor in a mouse model of amyotrophic lateral sclerosis

Kabashi¹,

Agar²,

Taylor

et al. 2004

Journal of Neurochemistry

132

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Mutations in the Cu/Zn-superoxide dismutase (SOD-1) gene are responsible for a familial form of amyotrophic lateral sclerosis (fALS). The present study demonstrated impaired proteasomal function in the lumbar spinal cord of transgenic mice expressing human SOD-1 with the ALS-causing mutation G93A (SOD-1 G93A ) compared to non-transgenic littermates (LM) and SOD-1 WT transgenic mice. Chymotrypsin-like activity was decreased as early as 45 days of age. By 75 days, chymotrypsin-, trypsin-, and caspase-like activities of the proteasome were impaired, at about 50% of control activity in lumbar spinal cord, but unchanged in thoracic spinal cord and liver. Both total and specific activities of the proteasome were reduced to a similar extent, indicating that a change in proteasome function, rather than a decrease in proteasome levels, had occurred. Similar decreases of total and specific activities of the proteasome were observed in NIH 3T3 cell lines expressing fALS mutants SOD-1 G93A and SOD- Wang et al. 2002), and patients with sporadic or fALS (Shibata et al. 1996;Kato et al. 2000). Proteinaceous inclusions are a common feature of several neurodegenerative disorders and their occurrence suggests an overload of protein chaperones and ubiquitin-proteasome pathways, which sequester, refold or degrade abnormal proteins (Kopito 2000;McNaught et al. 2001;Sherman and Goldberg 2001;Ciechanover and Brundin 2003). Mutant SOD-1 is catabolized by the proteasome (Hoffman et al. 1996;Johnston et al. 2000;Niwa et al. 2002), a nonlysosomal, proteolytic system responsible for about 80% of cellular proteolysis (Coux et al. 1996;Hershko and Ciechanover 1998). The 26S proteasome consists of a 20S catalytic core and two regulatory complexes, 19S or 11S (Adams et al. 1998;Cascio et al. 2002)

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Section: Introductionmentioning

confidence: 68%

Focal dysfunction of the proteasome: a pathogenic factor in a mouse model of amyotrophic lateral sclerosis

Kabashi¹,

Agar²,

Taylor

et al. 2004

Journal of Neurochemistry

132

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“…Oxidative modification of SOD-1 has been observed in Alzheimer, Parkinson, and fALS models (7,(15)(16)(17)(18)(19)(20)40). Such oxidative modification, however, should not be regarded as inherently toxic.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, Lewy body-like inclusions in sporadic ALS are immunoreactive with antibodies to SOD-1 (11)(12)(13). It has also been demonstrated that oxidative post-translational modification of SOD-1 occurs in vivo with aging (14) and in association with the fALS (7,(15)(16)(17), Parkinson (18), and Alzheimer (18) neurodegenerative diseases. There is also considerable evidence that fALS-causing mutations predispose SOD-1 to post-translational modifications (19 -21), and that in vitro oxidative modification of SOD-1 induces aggregation (22)(23)(24).…”

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confidence: 99%

Tryptophan 32 Potentiates Aggregation and Cytotoxicity of a Copper/Zinc Superoxide Dismutase Mutant Associated with Familial Amyotrophic Lateral Sclerosis

Taylor

Gibbs

Kabashi

et al. 2007

Journal of Biological Chemistry

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One familial form of the neurodegenerative disease, amyotrophic lateral sclerosis, is caused by gain-of-function mutations in the gene encoding copper/zinc superoxide dismutase (SOD-1). This study provides in vivo evidence that normally occurring oxidative modification to SOD-1 promotes aggregation and toxicity of mutant proteins. The oxidation of Trp-32 was identified as a normal modification being present in both wild-type enzyme and SOD-1 with the disease-causing mutation, G93A, isolated from erythrocytes. Mutating Trp-32 to a residue with a slower rate of oxidative modification, phenylalanine, decreased both the cytotoxicity of mutant SOD-1 and its propensity to form cytoplasmic inclusions in motor neurons of dissociated mouse spinal cord cultures. Amyotrophic lateral sclerosis (ALS)5 is an adult onset neurodegenerative disease in which two percent of all cases are caused by mutations in the gene encoding copper/zinc superoxide dismutase (SOD-1) (1). More than 100 mutations distributed throughout the structure of the protein introduce a toxic gain of function that decreases protein solubility, leading to aggregation and the formation of both detergent-insoluble SOD-1 (2, 3) and inclusions that are a histopathological hallmark of ALS (4 -8).The nature of the toxic gain of function imparted by familial ALS (fALS)-causing SOD-1 mutations is not completely understood (reviewed in Ref. 9). These mutations do, however, provide evidence that diverse and relatively minor changes in SOD-1 primary structure can cause fALS. Approximately ninety percent of ALS is sporadic, and it is plausible that posttranslational modification of wild-type proteins affects structural changes analogous to those caused by point mutation (10). Indeed, Lewy body-like inclusions in sporadic ALS are immunoreactive with antibodies to SOD-1 (11-13). It has also been demonstrated that oxidative post-translational modification of SOD-1 occurs in vivo with aging (14) and in association with the fALS (7, 15-17), Parkinson (18), and Alzheimer (18) neurodegenerative diseases. There is also considerable evidence that fALS-causing mutations predispose SOD-1 to post-translational modifications (19 -21), and that in vitro oxidative modification of SOD-1 induces aggregation (22-24).An understanding of how modifications that occur in vivo confer or potentiate toxic properties in proteins is lacking. Given the potential importance of post-translational modification of SOD-1, a study was designed to comprehensively characterize modifications that occur in vivo. Modification-prone residues in wild-type SOD-1 isolated from murine and human erythrocytes were identified and changed to residues that were less likely to be modified. Effects upon survival and aggregation were measured to determine whether preventing modification would attenuate the toxicity of SOD-1 with fALS-causing SOD-1 mutations. Tryptophan 32 (Trp-32) was shown to be modified in a significant fraction of as-isolated SOD-1. Herein we report that changing Trp-32 to a residue with a slower rate ...

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“…The major post-translational modifications of 20S subunits that have been detected in aging/senescence along with decreased proteasomal activity are carbonylation, conjugation with a lipid peroxidation product, glycation, and ubiquitination (Bulteau et al 2000;Keller et al 2000;Carrard et al 2003;Farout et al 2006). A general increase in these modifications has been observed in spinal cord of mutant SOD1 mice and ALS patients (Pedersen et al 1998;Kato et al 2000;Wang et al 2002;Perluigi et al 2005;Poon et al 2005), but association with specific proteasomal proteins has not been assessed. Our initial attempts to identify b subunit modifications in lumbar spinal cord of SOD1 G93A mice by western analysis, by immunoprecipitation with antibody to 4-hydroxy-2-nonenalmodified protein, or by isolating b subunits from 2-D gels and analysis by mass spectrometry have not been successful.…”

Section: Discussionmentioning

confidence: 99%

Proteasomes remain intact, but show early focal alteration in their composition in a mouse model of amyotrophic lateral sclerosis

Kabashi

Agar

Hong

et al. 2008

Journal of Neurochemistry

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In amyotrophic lateral sclerosis caused by mutations in Cu/Zn‐superoxide dismutase (SOD1), altered solubility and aggregation of the mutant protein implicates failure of pathways for detecting and catabolizing misfolded proteins. Our previous studies demonstrated early reduction of proteasome‐mediated proteolytic activity in lumbar spinal cord of SOD1G93A transgenic mice, tissue particularly vulnerable to disease. The purpose of this study was to identify any underlying abnormalities in proteasomal structure. In lumbar spinal cord of pre‐symptomatic mice [postnatal day 45 (P45) and P75], normal levels of structural 20S α subunits were incorporated into 20S/26S proteasomes; however, proteasomal complexes separated by native gel electrophoresis showed decreased immunoreactivity with antibodies to β3, a structural subunit of the 20S proteasome core, and β5, the subunit with chymotrypsin‐like activity. This occurred prior to increase in β5i immunoproteasomal subunit. mRNA levels were maintained and no association of mutant SOD1 with proteasomes was identified, implicating post‐transcriptional mechanisms. mRNAs also were maintained in laser captured motor neurons at a later stage of disease (P100) in which multiple 20S proteins are reduced relative to the surrounding neuropil. Increase in detergent‐insoluble, ubiquitinated proteins at P75 provided further evidence of stress on mechanisms of protein quality control in multiple cell types prior to significant motor neuron death.

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Advanced glycation endproduct-modified superoxide dismutase-1 (SOD1)-positive inclusions are common to familial amyotrophic lateral sclerosis patients with SOD1 gene mutations and transgenic mice expressing human SOD1 with a G85R mutation

Cited by 67 publications

References 77 publications

Focal dysfunction of the proteasome: a pathogenic factor in a mouse model of amyotrophic lateral sclerosis

Focal dysfunction of the proteasome: a pathogenic factor in a mouse model of amyotrophic lateral sclerosis

Tryptophan 32 Potentiates Aggregation and Cytotoxicity of a Copper/Zinc Superoxide Dismutase Mutant Associated with Familial Amyotrophic Lateral Sclerosis

Proteasomes remain intact, but show early focal alteration in their composition in a mouse model of amyotrophic lateral sclerosis

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