Parkin protects dopaminergic neurons from excessive Wnt/β-catenin signaling

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• 作者：Nina Rawal ; Olga Corti ; Paola Sacchetti ; Hector Ardilla-Osorio ; Bita Sehat ; Alexis Brice ; Ernest Arenas
• 关键词：Wnt ; β ; -Catenin ; Parkin ; Dopamine ; Neuron ; Midbrain ; Cell cycle ; Apoptosis
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2009
• 出版时间：23 October 2009
• 年：2009
• 卷：388
• 期：3
• 页码：473-478
• 全文大小：544 K

文摘

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 β-catenin protein levels in vivo. Stabilization of β-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 β-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 β-catenin-induced cell death.