Parkinson's disease-linked parkin mutation disrupts recycling of synaptic vesicles in human dopaminergic neurons.
Parkinson's disease-linked parkin mutation disrupts recycling of synaptic vesicles in human dopaminergic neurons.
复制标题
帕金森病相关的帕金突变会破坏人类多巴胺能神经元中突触小泡的回收。
DOI：
10.1016/j.neuron.2023.08.018
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发表时间：
2023
期刊：
影响因子：
16.2
通讯作者：
Krainc,Dimitri
中科院分区：
文献类型：
--
作者：
Song,Pingping;Peng,Wesley;Sauve,Veronique;Fakih,Rayan;Xie,Zhong;Ysselstein,Daniel;Krainc,Talia;Wong,YvetteC;Mencacci,NiccolòE;Savas,JeffreyN;Surmeier,DJames;Gehring,Kalle;Krainc,Dimitri
帕金森介导的线粒体自噬已被广泛研究，但帕金森突变是否通过其他机制参与帕金森病的发病机制仍未被探索。使用患者来源的多巴胺能神经元，我们发现Ca2+/钙调素依赖性蛋白激酶2 （CaMK2）在Ser9位点磷酸化导致帕金以神经元活性依赖的方式激活。激活的parkin泛素化synaptojanin-1，促进其与嗜内蛋白A1和突触囊泡循环的相互作用。帕金突变PD患者的神经元显示突触囊泡循环缺陷，导致有毒氧化多巴胺的积累，通过增强亲内啡素A1的表达而减弱。值得注意的是，与单独的纯合突变PINK1相比，杂合子parkin和纯合子pten诱导的激酶1 （PINK1）突变联合导致疾病发病更早，进一步强调了parkin在促进疾病中的PINK1独立作用。因此，本研究确定了人类多巴胺能突触中parkin选择性激活的途径，并强调了该机制在帕金森病发病机制中的重要性。
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.