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Co-editing PINK1 and DJ-1 Genes Via adeno-associated virus-delivered crispr/cas9 System in Adult Monkey Brain Elicits Classical Parkinsonian Phenotype

引用

Neuroscience Bulletin 2021年第9期37卷 1271-1288页

作者： 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 Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province Kunming Institute of ZoologyChinese Academy of Sciences650223 KunmingChina Institute of Neuroscience CAS Key Laboratory of Primate NeurobiologyState Key Laboratory of NeuroscienceChinese Academy of SciencesShanghai 200031China Institutes of Physical Science and Information Technology Anhui UniversityHefei 230601China Center for Excellence in Brain Science and Intelligence Technology Chinese Academy of SciencesShanghai 200031China National Resource Center for Non-human Primates Kunming Primate Research Centerand National Research Facility for Phenotypic and Genetic Analysis of Model Animals(Primate Facility)Kunming Institute of ZoologyChinese Academy of Sciences650107 KunmingChina Diagnostic Radiology Department 920 Hospital of the Joint Logistics Support Force of the PLAKunming 650032China Ultrasound diagnosis Department 920 Hospital of the Joint Logistics Support Force of the PLAKunming 650032China Sichuan Provincial People’s Hospital University of Electronic Science and Technology of ChinaChengdu 610072China Department of Rehabilitation Medicine The Second People’s Hospital of Yunnan ProvinceKunming 650021China National Clinical Research Center for Aging and Medicine Huashan HospitalFudan UniversityShanghai 200433China

Whether direct manipulation of Parkinson’s disease(PD)risk genes in the adult monkey brain can elicit a Parkinsonian phenotype remains an unsolved ***,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 *** 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 evidentα-synuclein pathology in the gene-edited *** contrast,the phenotype of their middle-aged counterparts,which also showed clear PD symptoms and pathological hallmarks,were less *** 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 *** results suggested that both genetic and aging factors played important roles in the development of PD in the *** 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.

关键词： Parkinson’s disease Monkey adeno-associated virus-delivered crispr/cas9 PINK1 DJ-1 Parkinsonian phenotype

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