Human Molecular Genetics

Human Molecular Genetics Advance Access published online on November 8, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi413

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© The Author 2005. Published by Oxford University Press. All rights reserved. The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org
Received September 21, 2005
Accepted November 2, 2005

Article

Stress-induced Alterations in Parkin Solubility Promote Parkin Aggregation and Compromise Parkin's Protective Function

Cheng Wang ¹, Han Seok Ko ², Bobby Thomas ², Fai Tsang ³, Katherine C.M. Chew ¹, Shiam-Peng Tay ⁴, Michelle W.L. Ho ⁴, Tit-Meng Lim ⁵, Tuck-Wah Soong ³, Olga Pletnikova ⁶, Juan Troncoso ⁷, Valina L. Dawson ⁸, Ted M. Dawson ⁸, and Kah-Leong Lim ^9*

¹ Neurodegeneration Research Lab, National Neuroscience Institute, Singapore; Departments of Biological Sciences, National University of Singapore, Singapore
² Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Departments of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
³ Departments of Physiology, National University of Singapore, Singapore
⁴ Neurodegeneration Research Lab, National Neuroscience Institute, Singapore
⁵ Departments of Biological Sciences, National University of Singapore, Singapore
⁶ Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
⁷ Departments of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
⁸ Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Departments of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Departments of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA
⁹ Neurodegeneration Research Laboratory, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433; Departments of Biological Sciences, National University of Singapore, Singapore

^* To whom correspondence should be addressed.
Kah-Leong Lim, E-mail: Kah_Leong_Lim{at}nni.com.sg

	Abstract

Mutations in parkin are currently recognized as the most common cause of familial Parkinsonism. Emerging evidence also suggest 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. Since 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-OHDA), 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.

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