帕金
品脱1
多巴胺能
神经科学
粒体自噬
帕金森病
LRRK2
突变
细胞生物学
多巴胺
疾病
生物
化学
医学
自噬
遗传学
基因
内科学
细胞凋亡
作者
Pingping Song,Wesley Peng,Véronique Sauvé,Rayan Fakih,Zhong Xie,Daniel Ysselstein,Talia Krainc,Yvette C. Wong,Niccolò E. Mencacci,Jeffrey N. Savas,D. James Surmeier,Kalle Gehring,Dimitri Krainc
出处
期刊:Neuron
[Elsevier]
日期:2023-12-01
卷期号:111 (23): 3775-3788.e7
被引量:8
标识
DOI:10.1016/j.neuron.2023.08.018
摘要
Parkin-mediated mitophagy has been studied extensively, but whether mutations in parkin contribute to Parkinson's disease pathogenesis through alternative mechanisms remains unexplored. Using patient-derived dopaminergic neurons, we found that phosphorylation of parkin by Ca2+/calmodulin-dependent protein kinase 2 (CaMK2) at Ser9 leads to activation of parkin in a neuronal-activity-dependent manner. Activated parkin ubiquitinates synaptojanin-1, facilitating its interaction with endophilin A1 and synaptic vesicle recycling. Neurons from PD patients with mutant parkin displayed defective recycling of synaptic vesicles, leading to accumulation of toxic oxidized dopamine that was attenuated by boosting endophilin A1 expression. Notably, combined heterozygous parkin and homozygous PTEN-induced kinase 1 (PINK1) mutations led to earlier disease onset compared with homozygous mutant PINK1 alone, further underscoring a PINK1-independent role for parkin in contributing to disease. Thus, this study identifies a pathway for selective activation of parkin at human dopaminergic synapses and highlights the importance of this mechanism in the pathogenesis of Parkinson's disease.
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