title: Parkin protects dopaminergic neurons from excessive Wnt/beta-catenin signaling.
abstract: 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: Laboratory of Molecular Neurobiology, MBB, DBRM, Karolinska Institute, Stockholm S-17177, Sweden.
authors: Nina
authors: N
authors: Rawal
authors: Olga
authors: O
authors: Corti
authors: Paola
authors: P
authors: Sacchetti
authors: Hector
authors: H
authors: Ardilla-Osorio
authors: Bita
authors: B
authors: Sehat
authors: Alexis
authors: A
authors: Brice
authors: Ernest
authors: E
authors: Arenas
mesh_terms: D000818:Animals; D017209:Apoptosis; D019556:COS Cells; D002522:Chlorocebus aethiops; D004298:Dopamine / Q000378:metabolism*; D051379:Mice; D008938:Mitosis; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051153:Wnt Proteins; D051176:beta Catenin; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D004298:Dopamine