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

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

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

Author: Weili YANG ¹ ; Xiangyu GUO ² ; Zhuchi TU ² ; Xiusheng CHEN ² ; Rui HAN ² ; Yanting LIU ² ; Sen YAN ² ; Qi WANG ² ; Zhifu WANG ² ; Xianxian ZHAO ² ; Yunpeng ZHANG ³ ; Xin XIONG ² ; Huiming YANG ² ; Peng YIN ² ; Huida WAN ³ ; Xingxing CHEN ² ; Jifeng GUO ⁴ ; Xiao-Xin YAN ⁵ ; Lujian LIAO ³ ; Shihua LI ² ; Xiao-Jiang LI ⁶
Author Information

1. Guangdong Key Laboratory of Non-human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, 510632, China. weiliyang12@jnu.edu.cn.
2. Guangdong Key Laboratory of Non-human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, 510632, China.
3. 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.
4. Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, China.
5. Department of Anatomy and Neurobiology, Xiangya School of Medicine, Central South University, Changsha, 410008, China.
6. Guangdong Key Laboratory of Non-human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, 510632, China. xjli33@jnu.edu.cn.
Publication Type:Research Support, Non-U.S. Gov't
Keywords: Parkinson’s disease; mitochondria; neurodegeneration; neurogenesis; non-human primates
From: Protein & Cell 2022;13(1):26-46
CountryChina
Language:English
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.