Formation of parkin aggregates and enhanced PINK1 accumulation during the pathogenesis of Parkinson's disease.
Parkinson's disease (PD) is a devastating neurodegenerative disease characterized by a distinct set of motor symptoms. Loss-of-function mutations in PTEN-induced kinase 1 (PINK1) or parkin have been linked to early-onset autosomal recessive forms of familial PD. We have recently shown that parkin (an E3 ubiquitin ligase) and PINK1 (a serine/threonine kinase) affect one other's stability, solubility, and tendency to form cytoprotective aggresomes (Um et al., 2009). Here we validated the functional relevance of this mutual interaction under pathologic PD conditions, by investigating the changes of expression and solubility of these factors in response to PD-linked toxins. Consistent with our previous cell culture data, exposure of human dopaminergic neuroblastoma SH-SY5Y cells to PD-linked toxins (1-methyl-4-phenylpyridinium ion, 6-hydroxydopamine, or MG132) reduced Nonidet P-40-soluble parkin levels and induced PINK1 accumulation. Consistent with our previous findings from parkin knockout mice, rat models of PD (6-hydroxydopamine-, rotenone-, or MG132-induced PD) were also associated with an increase in soluble and insoluble PINK1 levels as well as enhanced formation of parkin aggregates. These findings suggest that both PINK1 and parkin play important roles in regulating the formation of Lewy bodies during the pathogenesis of sporadic and familial PD.
Um
Ji Won
JW
Department of Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
Park
Hyun Jung
HJ
Song
Jihwan
J
Jeon
Iksoo
I
Lee
Gwang
G
Lee
Phil Hyu
PH
Chung
Kwang Chul
KC
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D004195:Disease Models, Animal; D006801:Humans; D007976:Leupeptins / Q000633:toxicity; D016631:Lewy Bodies / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D012995:Solubility; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
D015655:1-Methyl-4-phenylpyridinium; D007976:Leupeptins; D016627:Oxidopamine; D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde