Abstract
A hallmark of Parkinson's disease (PD) is the preferential loss of substantia nigra dopamine neurons. Here, we identify a new parkin interacting substrate, PARIS (ZNF746), whose levels are regulated by the ubiquitin proteasome system via binding to and ubiquitination by the E3 ubiquitin ligase, parkin. PARIS is a KRAB and zinc finger protein that accumulates in models of parkin inactivation and in human PD brain. PARIS represses the expression of the transcriptional coactivator, PGC-1α the PGC-1α target gene, NRF-1 by binding to insulin response sequences in the PGC-1α promoter. Conditional knockout of parkin in adult animals leads to progressive loss of dopamine (DA) neurons in a PARIS-dependent manner. Moreover, overexpression of PARIS leads to the selective loss of DA neurons in the substantia nigra, and this is reversed by either parkin or PGC-1α coexpression. The identification of PARIS provides a molecular mechanism for neurodegeneration due to parkin inactivation. PaperClip:
| Original language | English |
|---|---|
| Pages (from-to) | 689-702 |
| Number of pages | 14 |
| Journal | Cell |
| Volume | 144 |
| Issue number | 5 |
| DOIs | |
| State | Published - 4 Mar 2011 |
Bibliographical note
Funding Information:This work was supported by NS38377, NS048206, NS051764, and the Bachmann Strauss Dystonia and Parkinson's Disease Foundation. Y.L. is supported by Samsung Scholarship Foundation. T.M.D. is the Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases. The authors thank Drs. Xin Guo, Sathya Siram, and members of the Dawson laboratory for assistance and contributions to the manuscript. We also thank Drs. Alex Kolodkin, David Ginty, and Solomon H. Snyder for helpful suggestions.
