Oxidative modifications and aggregation of Cu,Zn-superoxide dismutase associated with Alzheimer and Parkinson diseases.
Although oxidative stress has been strongly implicated in the pathogenesis of Alzheimer disease (AD) and Parkinson disease (PD), the identities of specific protein targets of oxidative damage remain largely unknown. Here, we report that Cu,Zn-superoxide dismutase (SOD1), a key antioxidant enzyme whose mutations have been linked to autosomal dominant neurodegenerative disorder familial amyotrophic lateral sclerosis (ALS), is a major target of oxidative damage in AD and PD brains. By using a combination of two-dimensional gel electrophoresis, immunoblot analysis, and mass spectrometry, we have identified four human brain SOD1 isoforms with pI values of 6.3, 6.0, 5.7, and 5.0, respectively. Of these, the SOD1 pI 6.0 isoform is oxidatively modified by carbonylation, and the pI 5.0 isoform is selectively accumulated in AD and PD. Moreover, Cys-146, a cysteine residue of SOD1 that is mutated in familial ALS, is oxidized to cysteic acid in AD and PD brains. Quantitative Western blot analyses demonstrate that the total level of SOD1 isoforms is significantly increased in both AD and PD. Furthermore, immunohistochemical and double fluorescence labeling studies reveal that SOD1 forms proteinaceous aggregates that are associated with amyloid senile plaques and neurofibrillary tangles in AD brains. These findings implicate, for the first time, the involvement of oxidative damage to SOD1 in the pathogenesis of sporadic AD and PD. This work suggests that AD, PD, and ALS may share a common or overlapping pathogenic mechanism(s) that could potentially be targeted by similar therapeutic strategies.
Choi
Joungil
J
Department of Pharmacology, Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322-3090, USA.
Rees
Howard D
HD
Weintraub
Susan T
ST
Levey
Allan I
AI
Chin
Lih-Shen
LS
Li
Lian
L
D000368:Aged; D000544:Alzheimer Disease / Q000201:enzymology*; D001921:Brain / Q000201:enzymology; D005260:Female; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000201:enzymology; D010084:Oxidation-Reduction; D010300:Parkinson Disease / Q000201:enzymology*; D058225:Plaque, Amyloid / Q000201:enzymology; D013482:Superoxide Dismutase / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*
D013482:Superoxide Dismutase