RESEARCH DESCRIPTION

My laboratory has extensively used transgenic animal models to investigate the pathogenesis of Huntington disease and polyglutamine diseases. We are particularly interested in cell-type selective neuropathology caused by polyglutamine expanded proteins. We have generated transgenic mice, pigs and monkeys expressing mutant huntingtin and other neurodegenerative disease causing mutant genes.  We also used specific promoters to generate transgenic animal that express mutant HTT in selective cell types.  My initial work on Huntington disease was published in Neuron in 1993. With nearly 30 years research experience on HD and polyglutamine expansion diseases, I will lead our group to generate suitable disease models to investigate mechanisms and to find effective treatment for age-dependent neurodegenerative diseases.  

DEGREES & EDUCATION

BM(MD): Jiangxi Medical college (University Nanchang), 1983

Postdoctoral fellows: Oregon Health Sciences University, 1987-1991

                                   Johns Hopkin’s University, 1991-1996

SELECTED PUBLICATIONS

1.    Bradford J, Shin J-Y, Roberts M, Wang C-E, Li X-J, Li SH. Expression of mutant huntingtin in mouse brain astrocytes causes age-dependent neurological symptoms.Proc Natl Acad Sci USA. 106:22480-5, 2009. DOI: 10.1073/pnas.0911503106

2.   Yang S, Huang SS, Gaertig MA, Li X-J, Li SH. Age-dependent decrease in chaperone activity impairs MANF expression leading to Purkinje cell degeneration in inducible SCA17 mice. Neuron, 81, 349–365, 2014. DOI: 10.1016/j.neuron.2013.12.002

3.   Huang B, Wei, WJ, Wang GH, Geartig MA, Feng Y, Wang W, Li X-J and Li SH.Mutant huntingtin down-regulates Myelin Regulatory Factor-mediated myelin gene expression and affects mature oligodendrocytes. Neuron, 85(6):1212-26, 2015. doi: 10.1016/j.neuron.2015.02.026

4.   Hong Y. Zhao T, Li X-J and Li SH. Mutant Huntingtin Impairs BDNF Release from Astrocytes by Disrupting Rab3a GTP/GDP Exchange. J Neurosci.24;36(34):8790-801. 2016. DOI: 10.1523/JNEUROSCI.0168-16.2016 

5.   Yang S, Chang R, Yang H, Zhao T, Hong Y, Kong HE, Sun X, Qin Z, Jin P, Li SH, Li XJ. CRISPR/Cas9-mediated gene editing ameliorates neurotoxicity in mouse model of Huntington's disease.J Clin Invest. 2017 Jun 30;127(7):2719-2724. 2017. 

6.   Hong Y, Zhao T, Li XJ, Li SH. Mutant huntingtin inhibits αB-crystallin expression and impairs exosome secretion from astrocytes. J Neurosci.37 (39) 9550-9563, 2017. doi: 10.1523/JNEUROSCI.1418-17.2017 

7.   Yang Y, Yang S, Guo J, Cui Y, Tang B, Li XJ, Li SH. Synergistic Toxicity of Polyglutamine-Expanded TATA-Binding Protein in Glia and Neuronal Cells: Therapeutic Implications for Spinocerebellar Ataxia 17.  J Neurosci. 37(38):9101-9115, 2017 

8.   Guo JF, Cui YT, Yang Y, Tang BS, Li YJ, Jin P, Li X-J, Yang S, Li SH. Piperine ameliorates SCA17 neuropathology via enhancing MANF expression and reducing ER stress. Mol Neurodegener,DOI 10.1186/s13024-018-0236-x 2018 13:4. 

9.   Yan S, Tu Z, Liu, Fan N, Yang H, Yang S, Yang W, Zhao Y, Zhen Ouyang, Lai C, Yang HQ, Li L, Liu, Q, Shi H, Xu G, Zhao H, Wei H, Pei Z, Li SH*, Lai* L, Li X-J* A huntingtin knock-in pig model recapitulates features of selective neurodegeneration in Huntington's disease. Cell. 173 (4):  989-1002, 2018. 

10.  Liu Q, Huang S, Yin P, Yang S, Zhang J, Jing L, Cheng S, Tang B, Li X-J, Pan Y, Li SH. Cerebellum-enriched protein INPP5A contributes to selective neuropathology in mouse model of spinocerebellar ataxias type 17. Nature communications. 11(1): 1-13. 2020. doi.org/10.1038/s41467-020-14931-8. 

11.  Yang H, Yang S, Jing L, Huang L, Chen L, Zhao X, Yang W, Pan Y, Yin P, Qin Z, Tang B, Li SH, Li X-J. Truncation of mutant huntingtin in knock-in mice demonstrates exon1 huntingtin is a key pathogenic form. Nature communications. 11(1): 1-15. 2020. https://doi.org/10.1038/s41467-020-16318-1 

12.  Yin P, Liu Q, Pan Y, Yang Y, Yang S, Wei W, Chen X, Hong Y, Bai D, Li X-J, Li SH. Phosphorylation of myelin regulatory factor by PRKG 2 mediates demyelination in Huntington's disease. EMBO Reports. 21(6): e49783. 2020. Doi.org/10.15252/embr.201949783. 

13.  Yin P*, Bai D, Zhu L, Deng F, Guo X, Li B, Chen L, Li SH*, Li X-J*. Cytoplasmic TDP-43 impairs the activity of the ubiquitin-proteasome system. Experimental Neurology, 113833. 2021. doi.org/10.1016/j.expneurol.2021.113833