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| 1 | CRISPR/Cas9-mediated PINK1 deletion leads to neurodegeneration in rhesus monkeys显示文摘Dear Editor,PINK1 mutations cause autosomal recessive and early-onset Parkinson’s disease(PD)with selective neurodegeneration.Unfortunately,current PINK1 knockout(KO)mouse1,2 and pig models3,4 are unable to recapitulate the selective and overt neurodegeneration seen in PD patients.Furthermore,endogenous Pink1 in the mouse brain is expressed at very low levels and can only be detected via immunoprecipitation,5 meaning that PINK1’s function in the mammalian brain needs to be assessed using larger animals that are closer to humans.We previously used CRISPR/Cas9 to target the monkey gene in one-cell stage embryos.6 Using the same approach,we designed two gRNAs to target exon 2(T1)and exon 4(T2),which encode a kinase domain in the PINK1 gene of rhesus monkeys(Fig.1a).CRISPR/Cas9 and PINK1 gRNAs were injected into one-cell stage rhesus monkey embryos.A T7E1 assay and sequencing of PCR products from the injected embryos showed high efficiency(61.5%)in targeting PINK1(Fig.1b and Supplementary information,Fig.S1).Transfer of 87 embryos to 28 surrogate rhesus monkeys resulted in 11 pregnancies(39.2%)(Fig.1b).Eleven fetuses developed to term and were born naturally.Of these live monkeys,eight carried PINK1 mutations(M),and three were wild type(WT).However,three mutant monkeys(M1,M3 and M4)were newborn triplets that struggled to survive and died 3-4 days after birth.One WT newborn monkey also died after a difficult labor.Another mutant monkey(M2)died 7 days after birth without noticeable warning signs or symptoms.The other three mutant monkeys(M6,M7 and M8)have lived for three years;M5,however,reduced its food intake and showed weakness at the age of 1.5 years,and died 30 days after anesthesia for MRI examination. | Weili Yang Yunbo Liu Zhuchi Tu Chong Xiao Sen Yan Xishan Ma Xiangyu Guo Xiusheng Chen Peng Yin Zhengyi Yang Su Yang Tianzi Jiang Shihua Li Chuan Qin Xiao-Jiang Li | 2019 | Cell Research2019，29，4： | 12 |
| 2 | PINK1 kinase dysfunction triggers neurodegeneration in the primate brain without impacting mitochondrial homeostasis显示文摘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. | 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 | 2022 | Protein & Cell2022，13，1： | 3 |
| 3 | Generation of inactivated IL2RG and RAG1 monkeys with severe combined immunodeficiency using base editing显示文摘Severe combined immunodeficiency(SCiD)encompasses a range of inherited disorders that lead to a profound deterioration of the immune system.Among the pivotal genes associated with SCID,RAG1 and IL2RG play crucial roles.IL2RG is essential for the development,differentiation,and functioning of T,B,and NK cells,while RAG1 critically contributes to adaptive immunity by facilitating V(D)J recombination during the maturation of lymphocytes.Animal models carrying mutations in these genes exhibit notable deficiencies in their immune systems. | Xiao Zheng Chunhui Huang Yingqi Lin Bofeng Han Yizhi Chen Caijuan Li Jiawei Li Yongyan Ding Xichen Song Wei Wang Weien Liang Jianhao Wu Jiaxi Wu Jiale Gao Chengxi Wei Xudong Zhang Zhuchi Tu Sen Yan | 2023 | Signal Transduction and Targeted Therapy2023，8，10： | 0 |
| 4 | Tauopathy promotes spinal cord-dependent production of toxic amyloid-beta in transgenic monkeys显示文摘Tauopathy,characterized by the hyperphosphorylation and accumulation of the microtubule-associated protein tau,and the accumulation of Aβ oligomers,constitute the major pathological hallmarks of Alzheimer's disease.However,the relationship and causal roles of these two pathological changes in neurodegeneration remain to be defined,even though they occur together or independently in several neurodegenerative diseases associated with cognitive and movement impairment. | Zhuchi Tu Sen Yan Bofeng Han Cajuan Li Weien Liang Yingqi Lin Yongyan Ding Huiyi Wei Lu Wang Hao Xu Jianmeng Ye Bang Li Shihua Li Xiao-Jiang Li | 2023 | Signal Transduction and Targeted Therapy2023，8，10： | 0 |
| 5 | Large animal models for Huntington's disease research显示文摘Huntington'sdisease(HD)isahereditary neurodegenerative disorder for which there is currently no effectivetreatmentavailable.Consequently,the development of appropriate disease models is critical to thoroughly investigate disease progression.The genetic basis of HD involves the abnormal expansion of CAG repeats in the huntingtin(HTT)gene,leading to the expansion of a polyglutamine repeat in the HTT protein.Mutant HTT carrying the expanded polyglutamine repeat undergoes misfolding and forms aggregates in the brain,which precipitate selective neuronal loss in specific brain regions.Animal models play an important role in elucidating the pathogenesis of neurodegenerative disorders such as HD and in identifying potential therapeutic targets.Due to the marked species differences between rodents and larger animals,substantial efforts have been directed toward establishing large animal models for HD research.These models are pivotal for advancing the discovery of novel therapeutic targets,enhancing effective drug delivery methods,and improving treatment outcomes.We have explored the advantages of utilizing large animal models,particularly pigs,in previous reviews.Since then,however,significant progress has been made in developing more sophisticated animal models that faithfully replicate the typical pathology of HD.In the current review,we provide a comprehensive overview of large animal models of HD,incorporating recent findings regarding the establishment of HD knock-in(KI)pigs and their genetic therapy.We also explore the utilization of large animal models in HD research,with a focus on sheep,non-human primates(NHPs),and pigs.Our objective is to provide valuable insights into the application of these large animal models for the investigation and treatment of neurodegenerative disorders. | Bofeng Han Weien Liang Xiao-Jiang Li Shihua Li Sen Yan Zhuchi Tu | 2024 | Zoological Research2024，45，2： | 0 |
| 6 | 敲入亨廷顿基因的猪模型再现了亨廷顿病的选择性神经退化症状显示文摘文章简介亨廷顿舞蹈病(Huntington’s disease, HD)是一种遗传性神经退行性疾病,是由一种编码导致脑细胞死亡的毒性蛋白的基因引起的。尽管转基因小鼠已被广泛用于构建神经退行性疾病模型,但是它们缺乏在人类大脑中观察到的典型神经变性或明显的神经元缺失。 | Sen Yan Zhuchi Tu Zhaoming Liu Nana Fan Huiming Yang Su Yang Weili Yang Yu Zhao Zhen Ouyang Chengdan Lai Huaqiang Yang Li Li Qishuai Liu Hui Shi Guangqing Xu Heng Zhao Hongjiang Wei Zhong Pei 李世华 赖良学 李晓江 | 2019 | 科学新闻2019，0，2： | 0 |
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