Abstract

Mutations in the parkin gene underlie a familial form of Parkinson's disease known as autosomal recessive juvenile Parkinsonism (AR-JP). Dysfunction of parkin, a ubiquitin E3 ligase, has been implicated in the accumulation of ubiquitin proteasome system-destined substrates and eventually leads to cell death. However, regulation of parkin enzymatic activity is incompletely understood. Here we investigated whether the ubiquitin E3 ligase activity of parkin could be regulated by neddylation. We found that parkin could be a target of covalent modification with NEDD8, a ubiquitin-like posttranslational modifier. In addition, NEDD8 attachment caused an increase of parkin activity through the increased binding affinity for ubiquitin-conjugating E2 enzyme as well as the enhanced formation of the complex containing parkin and substrates. These findings point to the functional importance of NEDD8 and suggest that neddylation is one to the diverse modes of parkin regulation, potentially linking it to the pathogenesis of AR-JP.

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Publisher Full Text

Authors

Um JW, Han KA, Im E, Oh Y, Lee K, Chung KC

Institution

Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.

Source

Journal of neuroscience research 90:5 2012 May pg 1030-42

MeSH

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Animals
Cells, Cultured
Cycloheximide
Embryo, Mammalian
Gene Expression Regulation
Hippocampus
Humans
Immunoprecipitation
Leupeptins
Mutation
Neuroblastoma
Neurotoxins
Protein Binding
Protein Synthesis Inhibitors
RNA, Small Interfering
Rats
Sincalide
Stem Cells
Subcellular Fractions
Time Factors
Transfection
Ubiquitin-Protein Ligases
Ubiquitination
Ubiquitins

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22271254