Regulation of parkin and PINK1 by neddylation

Yeun Su Choo, George Vogler, Danling Wang, Sreehari Kalvakuri, Anton Iliuk, Weiguo Tao, Rolf Bodmer, Zhuohua Zhang

    Research output: Contribution to journalArticle

    34 Citations (Scopus)

    Abstract

    Neddylation is a posttranslational modification that plays important roles in regulating protein structure and function by covalently conjugating NEDD8, an ubiquitin-like small molecule, to the substrate. Here, we report that Parkinson's disease (PD)-related parkin and PINK1 are NEDD8 conjugated. Neddylation of parkin and PINK1 results in increased E3 ligase activity of parkin and selective stabilization of the 55 kDa PINK1 fragment. Expression of dAPP-BP1, a NEDD8 activation enzyme subunit, in Drosophila suppresses abnormalities induced by dPINK1 RNAi. PD neurotoxin MPP + inhibits neddylation of both parkin and PINK1. NEDD8 immunoreactivity is associated with Lewy bodies in midbrain dopaminergic neurons of PD patients. Together, these results suggest that parkin and PINK1 are regulated by neddylation and that impaired NEDD8 modification of these proteins likely contributes to PD pathogenesis.

    Original languageEnglish
    Article numberdds070
    Pages (from-to)2514-2523
    Number of pages10
    JournalHuman Molecular Genetics
    Volume21
    Issue number11
    DOIs
    Publication statusPublished - 2012

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