Journal Article

Stress-induced alterations in parkin solubility promote parkin aggregation and compromise parkin's protective function

Cheng Wang, Han Seok Ko, Bobby Thomas, Fai Tsang, Katherine C.M. Chew, Shiam-Peng Tay, Michelle W.L. Ho, Tit-Meng Lim, Tuck-Wah Soong, Olga Pletnikova, Juan Troncoso, Valina L. Dawson, Ted M. Dawson and Kah-Leong Lim

in Human Molecular Genetics

Volume 14, issue 24, pages 3885-3897
Published in print December 2005 | ISSN: 0964-6906
Published online November 2005 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddi413

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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.

Journal Article.  8025 words.  Illustrated.

Subjects: Genetics and Genomics

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