PARIS (ZNF746) Repression of PGC-1α Contributes to Neurodegeneration in Parkinson's Disease

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