Synaptotagmin-11 is a critical mediator of parkin-linked neurotoxicity and Parkinson’s disease-like pathology

Changhe Wang, Xinjiang Kang, Li Zhou, Zuying Chai, Qihui Wu, Rong Huang, Huadong Xu, Meiqin Hu, Xiaoxuan Sun, Suhua Sun, Jie Li, Ruiying Jiao, Panli Zuo, Lianghong Zheng, Zhenyu Yue and Zhuan Zhou ()
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Changhe Wang: Peking University
Xinjiang Kang: Peking University
Li Zhou: Peking University
Zuying Chai: Peking University
Qihui Wu: Peking University
Rong Huang: Peking University
Huadong Xu: Peking University
Meiqin Hu: Peking University
Xiaoxuan Sun: Peking University
Suhua Sun: Peking University
Jie Li: Peking University
Ruiying Jiao: Peking University
Panli Zuo: Peking University
Lianghong Zheng: Peking University
Zhenyu Yue: Icahn School of Medicine at Mount Sinai
Zhuan Zhou: Peking University

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-017-02593-y

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