State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine and Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, 100871, China.
Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China.
Nat Commun. 2018 Jan 8;9(1):81. doi: 10.1038/s41467-017-02593-y.
Loss-of-function mutations in Parkin are the most common causes of autosomal recessive Parkinson's disease (PD). Many putative substrates of parkin have been reported; their pathogenic roles, however, remain obscure due to poor characterization, particularly in vivo. Here, we show that synaptotagmin-11, encoded by a PD-risk gene SYT11, is a physiological substrate of parkin and plays critical roles in mediating parkin-linked neurotoxicity. Unilateral overexpression of full-length, but not C2B-truncated, synaptotagmin-11 in the substantia nigra pars compacta (SNpc) impairs ipsilateral striatal dopamine release, causes late-onset degeneration of dopaminergic neurons, and induces progressive contralateral motor abnormalities. Mechanistically, synaptotagmin-11 impairs vesicle pool replenishment and thus dopamine release by inhibiting endocytosis. Furthermore, parkin deficiency induces synaptotagmin-11 accumulation and PD-like neurotoxicity in mouse models, which is reversed by SYT11 knockdown in the SNpc or knockout of SYT11 restricted to dopaminergic neurons. Thus, PD-like neurotoxicity induced by parkin dysfunction requires synaptotagmin-11 accumulation in SNpc dopaminergic neurons.
Parkin 中的功能丧失突变是常染色体隐性帕金森病 (PD) 的最常见原因。已经报道了许多 parkin 的假定底物；然而，由于表征不佳，特别是在体内，它们的致病作用仍然不清楚。在这里，我们表明突触结合蛋白 11（encoded by a PD-risk gene SYT11）是 parkin 的生理底物，并在介导 parkin 相关神经毒性中发挥关键作用。在黑质致密部（SNpc）单侧过表达全长但不是 C2B 截断的突触结合蛋白 11 会损害同侧纹状体多巴胺释放，导致多巴胺能神经元迟发性变性，并诱导进行性对侧运动异常。在机制上，突触结合蛋白 11 通过抑制内吞作用来损害囊泡库的再补充，从而抑制多巴胺释放。此外，parkin 缺失在小鼠模型中诱导突触结合蛋白 11 积累和 PD 样神经毒性，这可以通过在 SNpc 中敲低 SYT11 或仅限于多巴胺能神经元的 SYT11 敲除来逆转。因此，parkin 功能障碍诱导的 PD 样神经毒性需要 SNpc 多巴胺能神经元中突触结合蛋白 11 的积累。
