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Co-editing PINK1 and DJ-1 genes via AAV-delivered CRISPR/Cas9 system in adult monkey brains elicits classic Parkinsonian phenotypes

Hao Li, Shihao Wu, Xia Ma, Xiao Li, Tianlin Cheng, Zhifang Chen, Jing Wu, Longbao Lv, Ling Li, Liqi Xu, Wenchao Wang, Yingzhou Hu, Haisong Jiang, Yong Yin, Zilong Qiu, Xintian Hu
doi: https://doi.org/10.1101/2020.09.19.305003
Hao Li
1Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China
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Shihao Wu
2Institute of Neuroscience, CAS Key Laboratory of Primate Neurobiology, State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai, 200031, China
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Xia Ma
1Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China
3Institute of Physical Science and Information Technology, Anhui University, Hefei, Anhui, 230601, China
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Xiao Li
2Institute of Neuroscience, CAS Key Laboratory of Primate Neurobiology, State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai, 200031, China
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Tianlin Cheng
2Institute of Neuroscience, CAS Key Laboratory of Primate Neurobiology, State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai, 200031, China
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Zhifang Chen
2Institute of Neuroscience, CAS Key Laboratory of Primate Neurobiology, State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai, 200031, China
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Jing Wu
1Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China
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Longbao Lv
5National Resource Center for Non-human Primates, Kunming Primate Research Center, and National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650107, China
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Ling Li
6Medical Imaging Department, 920 Hospital of Joint Logistics Support Force of PLA, Kunming, Yunnan, 650032, China
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Liqi Xu
7Special Diagnosis Department, 920 Hospital of Joint Logistics Support Force of PLA, Kunming, Yunnan, 650032, China
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Wenchao Wang
1Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China
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Yingzhou Hu
1Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China
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Haisong Jiang
8Sichuan Provincial People’s Hospital, and University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China
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Yong Yin
9Department of Rehabilitation Medicine, the Second People’s Hospital of Yunnan Province, Kunming, Yunnan, 650021, China
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  • For correspondence: yinyong@ynshhyy.com zqiu@ion.ac.cn xthu@mail.kiz.ac.cn
Zilong Qiu
2Institute of Neuroscience, CAS Key Laboratory of Primate Neurobiology, State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai, 200031, China
4CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China
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  • For correspondence: yinyong@ynshhyy.com zqiu@ion.ac.cn xthu@mail.kiz.ac.cn
Xintian Hu
1Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China
4CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China
5National Resource Center for Non-human Primates, Kunming Primate Research Center, and National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650107, China
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  • For correspondence: yinyong@ynshhyy.com zqiu@ion.ac.cn xthu@mail.kiz.ac.cn
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Abstract

Whether direct manipulation of Parkinson’s disease (PD) risk genes in monkey brain can elicit Parkinsonian phenotypes remains an unsolved issue. Here, we employed an adeno-associated virus (AAV)-delivered CRISPR/Cas9 system to directly co-edit PINK1 and DJ-1 genes in the substantia nigra (SN) region of four adult monkey brains. After the operation, two of the monkeys exhibited all classic PD symptoms, including bradykinesia, tremor, and postural instability, accompanied by severe nigral dopaminergic neuron loss (over 60%) and α-synuclein pathology. The aged monkeys were more vulnerable to gene editing by showing faster PD progression, higher final total PD scores, and severer pathologic changes compared with their younger counterparts, suggesting both the genetic and aging factors played important roles in PD development. This gene editing system can be used to develop a large quantity of genetically edited PD monkeys over a short period, thus providing a practical transgenic monkey model for future PD studies.

Competing Interest Statement

The authors have declared no competing interest.

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Posted September 20, 2020.
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Co-editing PINK1 and DJ-1 genes via AAV-delivered CRISPR/Cas9 system in adult monkey brains elicits classic Parkinsonian phenotypes
Hao Li, Shihao Wu, Xia Ma, Xiao Li, Tianlin Cheng, Zhifang Chen, Jing Wu, Longbao Lv, Ling Li, Liqi Xu, Wenchao Wang, Yingzhou Hu, Haisong Jiang, Yong Yin, Zilong Qiu, Xintian Hu
bioRxiv 2020.09.19.305003; doi: https://doi.org/10.1101/2020.09.19.305003
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Co-editing PINK1 and DJ-1 genes via AAV-delivered CRISPR/Cas9 system in adult monkey brains elicits classic Parkinsonian phenotypes
Hao Li, Shihao Wu, Xia Ma, Xiao Li, Tianlin Cheng, Zhifang Chen, Jing Wu, Longbao Lv, Ling Li, Liqi Xu, Wenchao Wang, Yingzhou Hu, Haisong Jiang, Yong Yin, Zilong Qiu, Xintian Hu
bioRxiv 2020.09.19.305003; doi: https://doi.org/10.1101/2020.09.19.305003

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