title: Stress-induced alterations in parkin solubility promote parkin aggregation and compromise parkin's protective function.
abstract: Mutations in parkin are currently recognized as the most common cause of familial Parkinsonism. Emerging evidence also suggests that parkin expression variability may confer a risk for the development of the more common, sporadic form of Parkinson's disease (PD). Supporting this, we have recently demonstrated that parkin solubility in the human brain becomes altered with age. As parkin apparently functions as a broad-spectrum neuroprotectant, the resulting decrease in the availability of soluble parkin with age may underlie the progressive susceptibility of the brain to stress. Interestingly, we also observed that many familial-PD mutations of parkin alter its solubility in a manner that is highly reminiscent of our observations with the aged brain. The converging effects on parkin brought about by aging and PD-causing mutations are probably not trivial and suggest that environmental modulators affecting parkin solubility would increase an individual's risk of developing PD. Using both cell culture and in vivo models, we demonstrate here that several PD-linked stressors, including neurotoxins (MPP+, rotenone, 6-hydroxydopamine), paraquat, NO, dopamine and iron, induce alterations in parkin solubility and result in its intracellular aggregation. Furthermore, the depletion of soluble, functional forms of parkin is associated with reduced proteasomal activities and increased cell death. Our results suggest that exogenously introduced stress as well as endogenous dopamine could affect the native structure of parkin, promote its misfolding, and concomitantly compromise its protective functions. Mechanistically, our results provide a link between the influence of environmental and intrinsic factors and genetic susceptibilities in PD pathogenesis.
authors.affiliation: Neurodegeneration Research Laboratory, National Neuroscience Institute, Singapore.
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.forename: Han Seok
authors.initials: HS
authors.lastname: Ko
authors.forename: Bobby
authors.initials: B
authors.lastname: Thomas
authors.forename: Fai
authors.initials: F
authors.lastname: Tsang
authors.forename: Katherine C M
authors.initials: KC
authors.lastname: Chew
authors.forename: Shiam-Peng
authors.initials: SP
authors.lastname: Tay
authors.forename: Michelle W L
authors.initials: MW
authors.lastname: Ho
authors.forename: Tit-Meng
authors.initials: TM
authors.lastname: Lim
authors.forename: Tuck-Wah
authors.initials: TW
authors.lastname: Soong
authors.forename: Olga
authors.initials: O
authors.lastname: Pletnikova
authors.forename: Juan
authors.initials: J
authors.lastname: Troncoso
authors.forename: Valina L
authors.initials: VL
authors.lastname: Dawson
authors.forename: Ted M
authors.initials: TM
authors.lastname: Dawson
authors.forename: Kah-Leong
authors.initials: KL
authors.lastname: Lim
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000473:pathology*; D002478:Cells, Cultured; D004298:Dopamine / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009603:Nitroso Compounds / Q000494:pharmacology; D010269:Paraquat / Q000494:pharmacology; D010300:Parkinson Disease / Q000235:genetics / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012016:Reference Values; D012402:Rotenone / Q000494:pharmacology; D012995:Solubility; D013312:Stress, Physiological; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry* / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
chemical_list: C093285:NOC 18; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D012402:Rotenone; D006861:Hydrogen Peroxide; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D046988:Proteasome Endopeptidase Complex; D010269:Paraquat; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine