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Title: Parkin protects dopaminergic neurons from excessive Wnt/{beta}-catenin signaling

Parkinson's disease (PD) is caused by degeneration of the dopaminergic (DA) neurons of the substantia nigra but the molecular mechanisms underlying the degenerative process remain elusive. Several reports suggest that cell cycle deregulation in post-mitotic neurons could lead to neuronal cell death. We now show that Parkin, an E3 ubiquitin ligase linked to familial PD, regulates {beta}-catenin protein levels in vivo. Stabilization of {beta}-catenin in differentiated primary ventral midbrain neurons results in increased levels of cyclin E and proliferation, followed by increased levels of cleaved PARP and loss of DA neurons. Wnt3a signaling also causes death of post-mitotic DA neurons in parkin null animals, suggesting that both increased stabilization and decreased degradation of {beta}-catenin results in DA cell death. These findings demonstrate a novel regulation of Wnt signaling by Parkin and suggest that Parkin protects DA neurons against excessive Wnt signaling and {beta}-catenin-induced cell death.
Authors:
 [1] ;  [2] ;  [3] ;  [1] ;  [2] ;  [3] ;  [4] ;  [2] ;  [3] ;  [3] ;  [1]
  1. Laboratory of Molecular Neurobiology, MBB, DBRM, Karolinska Institute, S-17177 Stockholm (Sweden)
  2. Universite Pierre et Marie Curie-Paris 6, CRICM UMR-S975, Inserm, U975 (France)
  3. (France)
  4. Cancer Center Karolinska, Karolinska Institute, S-17177 Stockholm (Sweden)
Publication Date:
OSTI Identifier:
22199845
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 388; Journal Issue: 3; Other Information: Copyright (c) 2009 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANIMALS; APOPTOSIS; CELL CYCLE; DEATH; DEREGULATION; DOPAMINE; GENE REGULATION; IN VIVO; LIGASES; NERVE CELLS; NERVOUS SYSTEM DISEASES