RGD Reference Report - Synaptotagmin-11 is a critical mediator of parkin-linked neurotoxicity and Parkinson's disease-like pathology. - Rat Genome Database

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

Authors: Wang, Changhe  Kang, Xinjiang  Zhou, Li  Chai, Zuying  Wu, Qihui  Huang, Rong  Xu, Huadong  Hu, Meiqin  Sun, Xiaoxuan  Sun, Suhua  Li, Jie  Jiao, Ruiying  Zuo, Panli  Zheng, Lianghong  Yue, Zhenyu  Zhou, Zhuan 
Citation: Wang C, etal., Nat Commun. 2018 Jan 8;9(1):81. doi: 10.1038/s41467-017-02593-y.
RGD ID: 14929208
Pubmed: (View Article at PubMed) PMID:29311685
DOI: Full-text: 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.

Annotation

Gene Ontology Annotations    

Biological Process

Objects Annotated

Genes (Rattus norvegicus)
Syt11  (synaptotagmin 11)


Additional Information