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S-nitrosylation of XIAP compromises neuronal survival in Parkinson's disease.
Tsang, Anthony H K; Lee, Yun-Il; Ko, Han Seok; Savitt, Joseph M; Pletnikova, Olga; Troncoso, Juan C; Dawson, Valina L; Dawson, Ted M; Chung, Kenny K K.
Afiliação
  • Tsang AH; Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong.
Proc Natl Acad Sci U S A ; 106(12): 4900-5, 2009 Mar 24.
Article em En | MEDLINE | ID: mdl-19273858
ABSTRACT
Inhibitors of apoptosis (IAPs) are a family of highly-conserved proteins that regulate cell survival through binding to caspases, the final executioners of apoptosis. X-linked IAP (XIAP) is the most widely expressed IAP and plays an important function in regulating cell survival. XIAP contains 3 baculoviral IAP repeats (BIRs) followed by a RING finger domain at the C terminal. The BIR domains of XIAP possess anticaspase activities, whereas the RING finger domain enables XIAP to function as an E3 ubiquitin ligase in the ubiquitin and proteasomal system. Our previous study showed that parkin, a protein that is important for the survival of dopaminergic neurons in Parkinson's disease (PD), is S-nitrosylated both in vitro and in vivo in PD patients. S-nitrosylation of parkin compromises its ubiquitin E3 ligase activity and its protective function, which suggests that nitrosative stress is an important factor in regulating neuronal survival during the pathogenesis of PD. In this study we show that XIAP is S-nitrosylated in vitro and in vivo in an animal model of PD and in PD patients. Nitric oxide modifies mainly cysteine residues within the BIR domains. In contrast to parkin, S-nitrosylation of XIAP does not affect its E3 ligase activity, but instead directly compromises its anticaspase-3 and antiapoptotic function. Our results confirm that nitrosative stress contributes to PD pathogenesis through the impairment of prosurvival proteins such as parkin and XIAP through different mechanisms, indicating that abnormal S-nitrosylation plays an important role in the process of neurodegeneration.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Doença de Parkinson / Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X / Neurônios / Compostos Nitrosos Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2009 Tipo de documento: Article País de afiliação: Hong Kong

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Doença de Parkinson / Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X / Neurônios / Compostos Nitrosos Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2009 Tipo de documento: Article País de afiliação: Hong Kong