PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in parkinson's disease

Joo Ho Shin, Han Seok Ko, Hochul Kang, Yunjong Lee, Yun Il Lee, Olga Pletinkova, Juan C. Troconso, Valina L. Dawson, Ted M. Dawson

Research output: Contribution to journalArticlepeer-review

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-1α 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. PaperClip:

Original languageEnglish (US)
Pages (from-to)689-702
Number of pages14
JournalCell
Volume144
Issue number5
DOIs
StatePublished - Mar 4 2011

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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