title: Regulation of parkin and PINK1 by neddylation.
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.
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Yeun Su
authors.initials: YS
authors.lastname: Choo
authors.forename: Georg
authors.initials: G
authors.lastname: Vogler
authors.forename: Danling
authors.initials: D
authors.lastname: Wang
authors.forename: Sreehari
authors.initials: S
authors.lastname: Kalvakuri
authors.forename: Anton
authors.initials: A
authors.lastname: Iliuk
authors.forename: W Andy
authors.initials: WA
authors.lastname: Tao
authors.forename: Rolf
authors.initials: R
authors.lastname: Bodmer
authors.forename: Zhuohua
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D059290:Dopaminergic Neurons / Q000378:metabolism; D004330:Drosophila / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D016631:Lewy Bodies / Q000378:metabolism; D008636:Mesencephalon / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
chemical_list: D029721:Drosophila Proteins; D017346:Protein Serine-Threonine Kinases; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; C534484:PINK1 protein, Drosophila; D000099202:PTEN-Induced Putative Kinase; C487430:park protein, Drosophila