期刊
NATURE COMMUNICATIONS
卷 9, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-017-02593-y
关键词
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资金
- National Key Research and Development Program of China [2016YFA0500401]
- National Basic Research Program of China [2012CB518006]
- National Natural Science Foundation of China [31228010, 31521062, 31327901, 31221002, 31330024, 31400708, 21790390, 21790394, 3171101198, 81571235, 31670843]
- Key Research and Development Program of Shannxi Province of China [2017SF-113]
- Fundamental Research Funds for the Central Universities of China [2017qngz10]
- NIH/NINDS [R01NS060123]
- Liaocheng University
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.
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