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

Changhe Wang,Xinjiang Kang,Li Zhou,Z. Chai,Qihui Wu,Rong Huang,Huadong Xu,Meiqin Hu,Xiaoxuan Sun,Suhua Sun,Jie Li,R. Jiao,Panli Zuo,Lianghong Zheng,Zhenyu Yue,Zhuan Zhou

Published 2018 in Nature Communications

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. Mutations in the parkin, an ubiquitin ligase, are linked to Parkinson’s disease. Here the authors show that synaptotagmin-11 is a parkin substrate and that its upregulation affects dopamine release, triggers degeneration, and causes motor impairment.

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