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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


  • Shin JH
  • Ko HS
  • Kang H
  • Lee Y
  • Lee YI
  • Pletinkova O
  • Troconso JC
  • Dawson VL
  • Dawson TM



Publication Data

March 4, 2011

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

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