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-1α and 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.
Pubmed ID: 21376232 RIS Download
Animals | Brain | Dopamine | Humans | Mice | Mice, Inbred C57BL | Mice, Knockout | NF-E2-Related Factor 1 | Neurodegenerative Diseases | Neurons | Nuclear Respiratory Factor 1 | Parkinson Disease | Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha | Rats | Repressor Proteins | Trans-Activators | Transcription Factors | Ubiquitin-Protein Ligases