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

Cell | Mar 4, 2011

http://www.ncbi.nlm.nih.gov/pubmed/21376232

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

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 | Transcription Factors | Ubiquitin-Protein Ligases

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Associated grants

  • Agency: NINDS NIH HHS, Id: NS048206
  • Agency: NINDS NIH HHS, Id: NS051764
  • Agency: NINDS NIH HHS, Id: NS38377
  • Agency: NINDS NIH HHS, Id: P50 NS038377
  • Agency: NINDS NIH HHS, Id: P50 NS038377-02
  • Agency: NINDS NIH HHS, Id: R01 NS048206
  • Agency: NINDS NIH HHS, Id: R01 NS048206-05
  • Agency: NINDS NIH HHS, Id: R01 NS048206-05S1

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