RESEARCH ARTICLE

PINK1 kinase dysfunction triggers neurodegeneration in the primate brain without impacting mitochondrial homeostasis

  • Weili Yang , 1 ,
  • Xiangyu Guo 1 ,
  • Zhuchi Tu 1 ,
  • Xiusheng Chen 1 ,
  • Rui Han 1 ,
  • Yanting Liu 1 ,
  • Sen Yan 1 ,
  • Qi Wang 1 ,
  • Zhifu Wang 1 ,
  • Xianxian Zhao 1 ,
  • Yunpeng Zhang 2 ,
  • Xin Xiong 1 ,
  • Huiming Yang 1 ,
  • Peng Yin 1 ,
  • Huida Wan 2 ,
  • Xingxing Chen 1 ,
  • Jifeng Guo 3 ,
  • Xiao-Xin Yan 4 ,
  • Lujian Liao 2 ,
  • Shihua Li 1 ,
  • Xiao-Jiang Li , 1
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  • 1. Guangdong Key Laboratory of Non-human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China
  • 2. Key Laboratory of Brain Functional Genomics of Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics, and Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 100021, China
  • 3. Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, China
  • 4. Department of Anatomy and Neurobiology, Xiangya School of Medicine, Central South University, Changsha 410008, China

Received date: 18 Aug 2021

Accepted date: 30 Sep 2021

Published date: 15 Jan 2022

Copyright

2021 The Author(s)

Abstract

In vitro studies have established the prevalent theory that the mitochondrial kinase PINK1 protects neurodegeneration by removing damaged mitochondria in Parkinson's disease (PD). However, difficulty in detecting endogenous PINK1 protein in rodent brains and cell lines has prevented the rigorous investigation of the in vivo role of PINK1. Here we report that PINK1 kinase form is selectively expressed in the human and monkey brains. CRISPR/Cas9-mediated deficiency of PINK1 causes similar neurodegeneration in the brains of fetal and adult monkeys as well as cultured monkey neurons without affecting mitochondrial protein expression and morphology. Importantly, PINK1 mutations in the primate brain and human cells reduce protein phosphorylation that is important for neuronal function and survival. Our findings suggest that PINK1 kinase activity rather than its mitochondrial function is essential for the neuronal survival in the primate brains and that its kinase dysfunction could be involved in the pathogenesis of PD.

Cite this article

Weili Yang , Xiangyu Guo , Zhuchi Tu , Xiusheng Chen , Rui Han , Yanting Liu , Sen Yan , Qi Wang , Zhifu Wang , Xianxian Zhao , Yunpeng Zhang , Xin Xiong , Huiming Yang , Peng Yin , Huida Wan , Xingxing Chen , Jifeng Guo , Xiao-Xin Yan , Lujian Liao , Shihua Li , Xiao-Jiang Li . PINK1 kinase dysfunction triggers neurodegeneration in the primate brain without impacting mitochondrial homeostasis[J]. Protein & Cell, 2022 , 13(1) : 26 -46 . DOI: 10.1007/s13238-021-00888-x

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