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.
Mesh Terms:
Animals, Brain, Dopamine, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, NF-E2-Related Factor 1, Neurodegenerative Diseases, Neurons, Nuclear Respiratory Factor 1, Parkinson Disease, Rats, Repressor Proteins, Trans-Activators, Ubiquitin-Protein Ligases
Cell
Date: Mar. 04, 2011
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