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

Author

Listed:
  • Changhe Wang

    (Peking University
    Xi’an Jiaotong University)

  • Xinjiang Kang

    (Peking University
    Liaocheng University
    Southwest Medical 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)

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.

Suggested Citation

  • 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 & Zh, 2018. "Synaptotagmin-11 is a critical mediator of parkin-linked neurotoxicity and Parkinson’s disease-like pathology," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-017-02593-y
    DOI: 10.1038/s41467-017-02593-y
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    Cited by:

    1. Benoît Delignat-Lavaud & Jana Kano & Charles Ducrot & Ian Massé & Sriparna Mukherjee & Nicolas Giguère & Luc Moquin & Catherine Lévesque & Samuel Burke & Raphaëlle Denis & Marie-Josée Bourque & Alex T, 2023. "Synaptotagmin-1-dependent phasic axonal dopamine release is dispensable for basic motor behaviors in mice," Nature Communications, Nature, vol. 14(1), pages 1-24, December.

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