Nitrosative stress linked to sporadic Parkinson's disease: S-nitrosylation of parkin regulates its E3 ubiquitin ligase activity.
Many hereditary and sporadic neurodegenerative disorders are characterized by the accumulation of aberrant proteins. In sporadic Parkinson's disease, representing the most prevalent movement disorder, oxidative and nitrosative stress are believed to contribute to disease pathogenesis, but the exact molecular basis for protein aggregation remains unclear. In the case of autosomal recessive-juvenile Parkinsonism, mutation in the E3 ubiquitin ligase protein parkin is linked to death of dopaminergic neurons. Here we show both in vitro and in vivo that nitrosative stress leads to S-nitrosylation of wild-type parkin and, initially, to a dramatic increase followed by a decrease in the E3 ligase-ubiquitin-proteasome degradative pathway. The initial increase in parkin's E3 ubiquitin ligase activity leads to autoubiquitination of parkin and subsequent inhibition of its activity, which would impair ubiquitination and clearance of parkin substrates. These findings may thus provide a molecular link between free radical toxicity and protein accumulation in sporadic Parkinson's disease.
Yao
Dongdong
D
Center for Neuroscience and Aging, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Gu
Zezong
Z
Nakamura
Tomohiro
T
Shi
Zhong-Qing
ZQ
Ma
Yuliang
Y
Gaston
Benjamin
B
Palmer
Lisa A
LA
Rockenstein
Edward M
EM
Zhang
Zhuohua
Z
Masliah
Eliezer
E
Uehara
Takashi
T
Lipton
Stuart A
SA
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000008:administration & dosage / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D015538:Nitrosation; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000378:metabolism*; D010449:Peptide Mapping; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012402:Rotenone / Q000008:administration & dosage / Q000378:metabolism; D026403:S-Nitrosothiols / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014475:Uncoupling Agents / Q000008:administration & dosage / Q000378:metabolism
D011993:Recombinant Fusion Proteins; D026403:S-Nitrosothiols; D025801:Ubiquitin; D014475:Uncoupling Agents; D012402:Rotenone; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein