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

doi:10.1007/s13238-021-00888-x

Protein Cell

2022, Vol. 13

Issue (1) : 26-46 https://doi.org/10.1007/s13238-021-00888-x

RESEARCH ARTICLE

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

Weili Yang¹(

), Xiangyu Guo¹, Zhuchi Tu¹, Xiusheng Chen¹, Rui Han¹, Yanting Liu¹, Sen Yan¹, Qi Wang¹, Zhifu Wang¹, Xianxian Zhao¹, Yunpeng Zhang², Xin Xiong¹, Huiming Yang¹, Peng Yin¹, Huida Wan², Xingxing Chen¹, Jifeng Guo³, Xiao-Xin Yan⁴, Lujian Liao², Shihua Li¹, Xiao-Jiang Li¹(

)

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

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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.

Keywords Parkinson's disease neurogenesis neurodegeneration mitochondria non-human primates

Corresponding Author(s): Weili Yang,Xiao-Jiang Li

About author:

Tongcan Cui and Yizhe Hou contributed equally to this work.

Online First Date: 20 December 2021 Issue Date: 14 February 2022

Cite this article:

Weili Yang,Xiangyu Guo,Zhuchi Tu, et al. PINK1 kinase dysfunction triggers neurodegeneration in the primate brain without impacting mitochondrial homeostasis[J]. Protein Cell, 2022, 13(1): 26-46.

URL:

https://academic.hep.com.cn/pac/EN/10.1007/s13238-021-00888-x
https://academic.hep.com.cn/pac/EN/Y2022/V13/I1/26

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