PARIS (ZNF746) repression of PGC-1? contributes to neurodegeneration in Parkinson's disease.

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-1? and the PGC-1? target gene, NRF-1 by binding to insulin response sequences in the PGC-1? 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-1? coexpression. The identification of PARIS provides a molecular mechanism for neurodegeneration due to parkin inactivation.

SUBMITTER: Shin JH 

PROVIDER: S-EPMC3063894 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature