Co-editing PINK1 and DJ-1 Genes Via Adeno-Associated Virus-Delivered CRISPR/Cas9 System in Adult Monkey Brain Elicits Classical Parkinsonian Phenotype.
10.1007/s12264-021-00732-6
- Author:
Hao LI
1
;
Shihao WU
1
;
Xia MA
1
;
Xiao LI
2
;
Tianlin CHENG
2
;
Zhifang CHEN
2
;
Jing WU
1
;
Longbao LV
3
;
Ling LI
4
;
Liqi XU
5
;
Wenchao WANG
1
;
Yingzhou HU
1
;
Haisong JIANG
6
;
Yong YIN
7
;
Zilong QIU
8
;
Xintian HU
9
Author Information
1. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, 650223, Kunming, China.
2. Institute of Neuroscience, CAS Key Laboratory of Primate Neurobiology, State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai, 200031, China.
3. National Resource Center for Non-human Primates, Kunming Primate Research Center, and National Research Facility for Phenotypic and Genetic Analysis of Model Animals (Primate Facility), Kunming Institute of Zoology, Chinese Academy of Sciences, 650107, Kunming, China.
4. Diagnostic Radiology Department, 920 Hospital of the Joint Logistics Support Force of the PLA, Kunming, 650032, China.
5. Ultrasound diagnosis Department, 920 Hospital of the Joint Logistics Support Force of the PLA, Kunming, 650032, China.
6. Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China.
7. Department of Rehabilitation Medicine, The Second People's Hospital of Yunnan Province, Kunming, 650021, China. yinyong@ynshhyy.com.
8. Institute of Neuroscience, CAS Key Laboratory of Primate Neurobiology, State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai, 200031, China. zqiu@ion.ac.cn.
9. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, 650223, Kunming, China. xthu@mail.kiz.ac.cn.
- Publication Type:Journal Article
- Keywords:
Adeno-associated virus-delivered CRISPR/Cas9;
DJ-1;
Monkey;
PINK1;
Parkinsonian phenotype;
Parkinson’s disease
- MeSH:
Animals;
Brain;
CRISPR-Cas Systems/genetics*;
Dependovirus/genetics*;
Haplorhini;
Phenotype;
Protein Kinases/genetics*
- From:
Neuroscience Bulletin
2021;37(9):1271-1288
- CountryChina
- Language:English
-
Abstract:
Whether direct manipulation of Parkinson's disease (PD) risk genes in the adult monkey brain can elicit a Parkinsonian phenotype remains an unsolved issue. Here, we used an adeno-associated virus serotype 9 (AAV9)-delivered CRISPR/Cas9 system to directly co-edit PINK1 and DJ-1 genes in the substantia nigras (SNs) of two monkey groups: an old group and a middle-aged group. After the operation, the old group exhibited all the classic PD symptoms, including bradykinesia, tremor, and postural instability, accompanied by key pathological hallmarks of PD, such as severe nigral dopaminergic neuron loss (>64%) and evident α-synuclein pathology in the gene-edited SN. In contrast, the phenotype of their middle-aged counterparts, which also showed clear PD symptoms and pathological hallmarks, were less severe. In addition to the higher final total PD scores and more severe pathological changes, the old group were also more susceptible to gene editing by showing a faster process of PD progression. These results suggested that both genetic and aging factors played important roles in the development of PD in the monkeys. Taken together, this system can effectively develop a large number of genetically-edited PD monkeys in a short time (6-10 months), and thus provides a practical transgenic monkey model for future PD studies.
