期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 21, 页码 5576-5581出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1717590115
关键词
Parkinson's disease; LRRK2; auxilin; synaptic vesicle endocytosis; DA oxidation
资金
- National Institutes of Health [R01 NS076054, R01 NS096240, 2T32AG020506-16]
- human embryonic and induced pluripotent Stem Cell Core Facility at Northwestern University (NIH) [P30 NS081774]
- Center for Advanced Microscopy of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University (National Cancer Institute Cancer Center Support) [P30 CA060553]
Recently identified Parkinson's disease (PD) genes involved in synaptic vesicle endocytosis, such as DNAJC6 (auxilin), have further implicated synaptic dysfunction in PD pathogenesis. However, how synaptic dysfunction contributes to the vulnerability of human dopaminergic neurons has not been previously explored. Here, we demonstrate that commonly mutated, PD-linked leucine-rich repeat kinase 2 (LRRK2) mediates the phosphorylation of auxilin in its clathrin-binding domain at Ser627. Kinase activity-dependent LRRK2 phosphorylation of auxilin led to differential clathrin binding, resulting in disrupted synaptic vesicle endocytosis and decreased synaptic vesicle density in LRRK2 patient-derived dopaminergic neurons. Moreover, impaired synaptic vesicle endocytosis contributed to the accumulation of oxidized dopamine that in turn mediated pathogenic effects such as decreased glucocerebrosidase activity and increased alpha-synuclein in mutant LRRK2 neurons. Importantly, these pathogenic phenotypes were partially attenuated by restoring auxilin function in mutant LRRK2 dopaminergic neurons. Together, this work suggests that mutant LRRK2 disrupts synaptic vesicle endocytosis, leading to altered dopamine metabolism and dopamine-mediated toxic effects in patient-derived dopaminergic neurons.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据