Human Molecular Genetics Advance Access originally published online on November 8, 2005
Human Molecular Genetics 2005 14(24):3885-3897; doi:10.1093/hmg/ddi413
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Stress-induced alterations in parkin solubility promote parkin aggregation and compromise parkin's protective function
1Neurodegeneration Research Laboratory, National Neuroscience Institute, Singapore, 2Department of Biological Sciences and 3Department of Physiology, National University of Singapore, Singapore, 4Institute for Cell Engineering, 5Department of Neurology, 6Department of Neuroscience and 7Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
* To whom correspondence should be addressed at: Neurodegeneration Research Laboratory, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore. Tel: +65 63577520; Fax: +65 62569178; Email: kah_leong_lim{at}nni.com.sg
Received September 21, 2005; Accepted November 2, 2005
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.
These authors contributed equally to this work.
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