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

Cell | 2011

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

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Associated grants

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

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Jalview (tool)

RRID:SCR_006459

A free program for multiple sequence alignment editing, visualisation and analysis that is available in two forms: a lightweight Java applet for use in web applications, and a powerful desktop application that employs web services for sequence alignment, secondary structure prediction and the retrieval of alignments, sequences, annotation and structures from public databases and any DAS 1.53 compliant sequence or annotation server. Use it to view and edit sequence alignments, analyse them with phylogenetic trees and principal components analysis (PCA) plots and explore molecular structures and annotation. Jalview has built in DNA, RNA and protein sequence and structure visualisation and analysis capabilities. It uses Jmol to view 3D structures, and VARNA to display RNA secondary structure.

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