RESEARCH DESCRIPTION

My current research fields include use of genetically modified animals (mouse, pig, monkey) to investigate the pathogenesis of important brain diseases and to develop their treatments. Genetically modified animal models have been extensively used to investigate the pathogenesis of age-dependent neurodegenerative diseases, such as Alzheimer (AD), Parkinson (PD), Huntington (HD) diseases, and Amyotrophic lateral sclerosis (ALS). The common feature of these diseases is the age-dependent accumulation of misfolded proteins in the brain, which can be recapitulated in a variety of animal models of neurodegenerative diseases. However, the brains of transgenic mouse models of AD, PD, and HD do not show the striking neuronal loss or degeneration that is a typical pathological feature in patient brains. Species differences between small animals and humans may account for differential pathology in transgenic animal models and patient brains. Using CRISPR/Cas9 to modify the endogenous disease genes in large animals (pigs and monkeys), we demonstrate that typical neuropathological features can be mimicked in the brains of large animals.  The findings underscore the importance of using large mammals to investigate the pathogenesis of important brain diseases and their therapeutics.

DEGREES & EDUCATION

BM (MD), Jiangxi Medical College, 1983

MSc, Suzhou Medical College, 1986

PhD, Oregon Health Science University, Portland USA, 1991

Postdoctoral fellow, Johns Hopkins University 1991-1995

ACADEMIC APPOINTMENTS

1995-1996           Assistant Professor           Department of Psychiatry, Johns Hopkins

                                                                      University School of Medicine

1996-2001           Assistant Professor           Department of Genetics, Emory University

2001-2005           Associate Professor           Department of Human Genetics, Emory

                                                                       University School of Medicine

2005-2019           Professor                           Department of Human Genetics, Emory

                                                                       University School of Medicine

2007-2019           Distinguished Professor

of Human Genetics           Emory University

2012-2016     Investigator                             Institute of Genetics and Developmental  

Biology, Chinese Academy of Science 

2017-present      Professor                            GHM Institute of CNS Regeneration, Jinan

                                                                      University, Guangzhou, China

RECENT SELECTED PUBLICATIONS

2023

Jia QQ, Bai DZ, Zheng X, Zhu LH, Ou KL, Wang X, Tong HC, Zhang YR, Wang J, Zeng J, Yan S, Li SH, Li XJ, Yin P. Comparing HD knock-in pigs and mice reveals the pathological role of IL-17 Cell Rep 2023. 2023 Dec 26;42(12):113443.

Zhu L, Li S, Li XJ, Yin P. Pathological insights from amyotrophic lateral sclerosis animal models: comparisons, limitations, and challenges. Transl Neurodegener. 2023 Sep 20;12(1):46. 

Tu Z, Yan S, Han BF, Li CJ, Liang WA, Lin YQ, Ding YY, Wei HY, Wang L, Xu H, Ye JM, Li B, Li SH, Li XJ. Tauopathy promotes spinal cord-dependent production of toxic amyloid-beta in transgenic monkeys. Signal Transduct Target Ther 2023 Sep 22;8(1):358. 2023  

Li C, Lin Y, Chen Y, Song X, Zheng X, Li J, He J, Chen X, Huang C, Wang W, Wu J, Wu J, Gao J, Tu Z, Li XJ, Yan S, Li S. A Specific Mini-Intrabody Mediates Lysosome Degradation of Mutant Huntingtin. Adv Sci (Weinh). 2023 Sep 8:e2301120

Yan S, Zheng X, Lin YQ, Li CJ, Liu ZM, Li JW, Tu ZC, Zhao Y, Huang CH, Chen YZ, Li J, Song XC, Han BF, Wang W, Liang WE, Lai LX, Li XJ, LI SH. Cas9-mediated replacement of expanded CAG repeats in a pig model of Huntington’s disease. Nat Biomed Eng. 2023 Feb 16. doi: 10.1038/s41551-023-01007-3. Online ahead of print.

Li B, Zhao H, Tu Z, Yang W, Han R, Wang L, Luo X, Pan M, Chen X, Zhang J, Xu H, Guo X, Yan S, Yin P, Zhao Z, Liu J, Luo Y, Li Y, Yang Z, Zhang B, Tan Z, Xu H, Jiang T, Jiang YH, Li S, Zhang YQ, Li XJ. CHD8 mutations increase gliogenesis to enlarge brain size in the nonhuman primate. Cell Discov. 2023 Mar 7;9(1):27.

Bai D, Zhu L, Jia Q, Duan X, Chen L, Wang X, Hou J, Jiang G, Yang S, Li S, Li XJ, Yin P. Loss of TDP-43 promotes somatic CAG repeat expansion in Huntington's disease knock-in mice. Prog Neurobiol. 2023 Jun 12:102484.

2022

Yang W, Guo X, Tu Z, Chen X, Han R, Liu Y, Yan S, Wang Q, Wang Z, Zhao X, Zhang Y, Xiong X, Yang H, Yin P, Wan H, Chen X, Guo J, Yan XX, Liao L, Li S, Li XJ. PINK1 kinase dysfunction triggers neurodegeneration in the primate brain without impacting mitochondrial homeostasis. Protein and Cell   2022 Jan;13(1):26-46. Epub 2021 Nov 20

Chen XX, Su YZ, Chen LQ, Che XS, Pan MT, Zhang YR, Wang Q, Yang WL, Yin P, He DJ, Guo XY, Yang S, Zhen Y, Yan S, Li XJ, LI SH. Differential expression and roles of Huntingtin and Huntingtin-associated protein 1 in the mouse and primate brains. Cell Mol Life Sci. 2022 Oct 17;79(11):554.

Han R, Liu YT, Li SH, Li XJ, Yang WL. PINK1/Parkin-mediated mitophagy: differences between in vitro and in vivo models. Autophagy. 2022 Nov 3:1-10.

Yang WL, Li S, Li XJ. AHI1: linking depression and impaired antiviral immune response. Cell Res. 2022 Oct;32(10):869-870.

Yin P, Li S, Li XJ, Yang W. New pathogenic insights from large animal models of neurodegenerative diseases. Protein Cell. 2022 Oct;13(10):707-720.

2021

Yin P, Bai DZ, Deng FY, Zhang C, Jia QQ, Zhu LH, Chen LQ, Li B, Guo XY, Ye JM, Tan ZQ, Wang L, Li SH, Li XJ. SQSTM1 mediated clearance of cytoplasmic mutant TARDBP/TDP-43 in the monkey brain. Autophagy Dec 22:1-14. 2021

Yang WL, Chen XS, Li SH, Li XJ. Genetically modified large animal models for investigating neurodegenerative diseases. Cell & Bioscience Dec 21;11(1):218, 2022.

Yang W, Guo X, Tu Z, Chen X, Han R, Liu Y, Yan S, Wang Q, Wang Z, Zhao X, Zhang Y, Xiong X, Yang H, Yin P, Wan H, Chen X, Guo J, Yan XX, Liao L, Li S, Li XJ. PINK1 kinase dysfunction triggers neurodegeneration in the primate brain without impacting mitochondrial homeostasis. Protein and Cell   2021 Nov 20. doi: 10.1007/s13238-021-00888-x.

Yin P, Bai D, Zhu L, Deng F, Guo X, Li B, Chen L, Li S, Li XJ. Cytoplasmic TDP-43 impairs the activity of the ubiquitin-proteasome system. Exp Neurol. 2021 Aug 4:113833.

Jing L, Cheng S, Pan Y, Liu Q, Yang W, Li S, Li XJ. Accumulation of endogenous mutant huntingtin in astrocytes exacerbates neuropathology of Huntington disease in mice. Mol Neurobiol. 2021 Jul 12. doi: 10.1007/s12035-021-02451-5. Online ahead of print.

Bai D, Yin P, Zhang Y, Sun F, Chen L, Lin L, Yan S, Li S, Li XJ. Lack of association of somatic CAG repeat expansion with striatal neurodegeneration in HD knock-in animal models. Hum Mol Genet. 2021 May 5:ddab129.

Wang B, Xin N, Qian X, Zhai L, Miao Z, Yang Y, Li S, Sun M, Xu X, Li XJ. Ahi1 regulates the nuclear translocation of glucocorticoid receptor to modulate stress response. Transl Psychiatry. 2021 Mar 29;11(1):188.

Zhang XY, Li J, Li CJ, Lin YQ, Huang CH, Zheng X, Song XC, Tu ZC, Li XJ, Yan S. Differential development and electrophysiological activity in cultured cortical neurons from the mouse and cynomolgus monkey. Neural Regen Res. 2021 Dec;16(12):2446-2452.

2020

Liu Q, Cheng SY, Yang HM, Zhu LY, Pan YC, Jing L, Tang BS, Li SH, Li X-J. Loss of Hap1 selectively promotes striatal degeneration in Huntington disease mic. Proc Natl Acad Sci U S A. 2020, 117(33):20265-20273.

Chen XX, Xin N, Pan YC, Zhu LY, Yin P, Liu Q, Yang WL, Xu XS, Li Sh, Li XJ. Huntingtin-associated protein 1 in mouse hypothalamus stabilizes glucocorticoid receptor in stress response. Front Cell Neurosci. Jun 4;14:125, 2020

Yang HM, Yang S, Jing L, Huang LX, Chen LX, Zhao XX, Yang WL, Pan YC, Yin P, Qin Z, Li SH, Li X-J. Truncation of mutant huntingtin in knock-in mice demonstrates exon1 huntingtin is a key pathogenic form. Nat Commun. 2020 May 22;11(1):2582.

Yin P, Liu Q, Pan Y, Yang W, Yang S, Wei W, Chen X, Hong Y, Bai D, Li XJ, Li S.  Phosphorylation of myelin regulatory factor by PRKG2 mediates demyelination in Huntington's disease.  EMBO Rep. 2020 Apr 9:e49783. doi: 10.15252.

Liu Q, Huang S, Yin P, Yang S, Zhang J, Jing L, Cheng S, Tang B, Li XJ, Pan Y, Li S. Cerebellum-enriched protein INPP5A contributes to selective neuropathology in mouse model of spinocerebellar ataxias type 17. Nat Commun. 2020 Feb 27;11(1):1101.

Yang S, Yang H, Huang L, Chen L, Qin Z, Li S, Li XJ. Lack of RAN-mediated toxicity in Huntington's disease knock-in mice. Proc Natl Acad Sci U S A. 2020 Feb 25;117(8):4411-4417.

2019

Zhu LY, Chen LQ, Yan LY Perkins BD, Li SH, Li BM, Xu HA, Li X-J. Mutant Ahi1 affects retinal axon projection in zebrafish via toxic gain of function. Front Cell Neurosci. 2019 Mar 21;13:81. doi: 10.3389/fncel.2019.00081. 2019

Yin P, Gao XY, Yang WL, Yan S, Yang S, Zhao T, Q Sun, Liu YB, Li SH, Li X-J. Caspase-4 mediates cytoplasmic accumulation of mutant TDP-43 in the non-human primate brain. Acta Neuropathol 2019 137(6):919-937.

Yang W, Liu YB, Tu ZC, Xiao C, Yan S, Ma XS, Guo XY, Chen XS, Yin P, Yang ZY, Yang S, Jiang TZ, Li SH, Qin C, Li X-J. CRISPR/Cas9-mediated PINK1 deletion leads to neurodegeneration in rhesus monkeys. Cell Res, 29(4):334-336 2019

Yang W, Li SH, Li X-J. A CRISPR monkey model reveals a unique function of PINK1 in primate brains.  Mol Neurodegener. 14:17, 2019

2018

Yang S, Li S, Li X-J. Shortening the half-life of Cas9 maintains its gene editing ability and reduces neuronal toxicity. Cell Rep, 25, 2653–2659, 2018

Tu ZC, Zhao H, Li B, Yan S, Wang L, Tang YJ, Li ZJ, Bai DZ, Li CJ, Lin YQ, Li YF, Liu JR, Xu H, Guo XY, Jiang YH, Zhang YQ, Li X-J. CRISPR/Cas9-mediated disruption of SHANK3 in monkey leads to drug-treatable autism-like symptoms. Hum Mol Genet, 2018; 28(4):561-571.

Yan S, Tu ZC, Liu ZM, Fan NN, Yang WL, Zhao Y, Ouyan Z, Lai CD, Yang HQ, Li L, Shi H, Xu GQ, Zhao H, Wei HJ, Pei Z, Li SH, Lai LX, Li X-J. A huntingtin knock-in pig model recapitulates features of selective neurodegeneration in Huntington’s disease. Cell 173(4):989-1002. 2018

Guo JF, Cui YT, Yang Y, Tang BS, Li YJ, Jin P, Li XJ, Yang S, Li SH. Piperine ameliorates SCA17 neuropathology via enhancing MANF expression and reducing ER stress. Mol Neurodegener. 2018 Jan 30;13(1):4.