[HTML][HTML] PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in Parkinson's disease

JH Shin, HS Ko, H Kang, Y Lee, YI Lee, O Pletinkova… - Cell, 2011 - cell.com
JH Shin, HS Ko, H Kang, Y Lee, YI Lee, O Pletinkova, JC Troconso, VL Dawson, TM Dawson
Cell, 2011cell.com
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 …
Summary
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.
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