Journal
JOURNAL OF NEUROSCIENCE
Volume 25, Issue 8, Pages 2002-2009Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.4474-04.2005
Keywords
parkin; synphilin-1; ubiquitin; Parkinson's disease; Lewy body; dopamine
Categories
Funding
- NINDS NIH HHS [P50 NS038377, NS48206, NS38377, P01 NS016375, NS16375, R01 NS048206] Funding Source: Medline
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It is widely accepted that the familial Parkinson's disease ( PD)- linked gene product, parkin, functions as a ubiquitin ligase involved in protein turnover via the ubiquitin - proteasome system. Substrates ubiquitinated by parkin are hence thought to be destined for proteasomal degradation. Because we demonstrated previously that parkin interacts with and ubiquitinates synphilin- 1, we initially expected synphilin- 1 degradation to be enhanced in the presence of parkin. Contrary to our expectation, we found that synphilin- 1 is normally ubiquitinated by parkin in a nonclassical, proteasomal- independent manner that involves lysine 63 ( K63)- linked polyubiquitin chain formation. Parkin- mediated degradation of synphilin- 1 occurs appreciably only at an unusually high parkin to synphilin- 1 expression ratio or when primed for lysine 48 ( K48)- linked ubiquitination. In addition we found that parkin- mediated ubiquitination of proteins within Lewy- body- like inclusions formed by the coexpression of synphilin- 1, alpha- synuclein, and parkin occurs predominantly via K63 linkages and that the formation of these inclusions is enhanced by K63- linked ubiquitination. Our results suggest that parkin is a dual- function ubiquitin ligase and that K63- linked ubiquitination of synphilin- 1 by parkinmaybe involved in the formation of Lewy body inclusions associated with PD.
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