No. 24

Time：9:30 AM, April 24, 2024 (Wednesday)

Location: Yifu Lecture Hall, North Basic Research Building 

Host: Lin Mei

     Chinese Institutes for Medical Research, Beijing

Speaker: Xiao-Jiang Li 

Professor

Guangdong-Hongkong-Macau Institute of CNS Regeneration,                 Jinan University 

Title: Use of monkey models to investigate brain diseases

Abstract:

Genetically modified animal models have been extensively utilized to explore the progression of age-related neurodegenerative conditions, including Alzheimer's (AD), Parkinson's (PD), Huntington's (HD) diseases, and Amyotrophic lateral sclerosis (ALS). These diseases share a common feature of age-related accumulation of misfolded proteins in the brain, a phenomenon replicated in various mouse models of neurodegenerative diseases. However, transgenic mouse models of AD, PD, and HD do not exhibit the pronounced neuronal loss or degeneration typically seen in patient brains. Discrepancies in pathology between transgenic mouse models and human brains may be attributed to species differences between small animals and humans. By utilizing CRISPR/Cas9 to express the disease genes in large animals such as monkeys, we can replicate typical neuropathological features in the brains of the larger animals. These results emphasize the significance of employing non-human primates to investigate the progression of significant brain disorders and their treatments.

Selected Papers:

1. Yin P, Guo X, Yang W, Yan S, Yang S, Zhao T, Sun Q, Liu Y, Li S, Li XJ. Caspase-4 mediates cytoplasmic accumulation of TDP-43 in the primate brains. Acta Neuropathol. 2019 Jun;137(6):919-937.
2. 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.
3. Tu Z, Yan S, Han B, Li C, Liang W, Lin Y, Ding Y, Wei H, Wang L, Xu H, Ye J, Li B, Li S, 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.   

Speaker: Shihua Li 

Professor

Guangdong-Hongkong-Macau Institute of CNS Regeneration,                 Jinan University

Title: Huntington Disease Therapy by Targeting HTT

Abstract:

Huntington’s disease (HD) is caused by the abnormal expansion of CAG repeats in the huntingtin gene (HTT), leading to the production of the mutant huntingtin protein (mHTT) containing a polyglutamine sequence in its N-terminus. The pathogenic mechanisms driving HD are complex and not entirely understood. While mouse models carrying mutant HTT offer valuable insights into HD pathogenesis, many of these models do not exhibit the pronounced neurodegeneration typical of HD patients. We have established HD knock-in pigs that faithfully replicate selective neurodegeneration seen in HD. Employing gene therapy to eliminate the mutant gene in HD knock-in pigs can produce effective therapeutic outcomes. Additionally, we have developed a strategy to target mutant HTT using an intracellular antibody directed to the lysosome for degradation, demonstrating promising therapeutic effects on HD pathology.

Selected Papers:

1. Yan S, Tu Z, Liu Z, Fan N, Yang H, Yang S, Yang W, Zhao Y, Ouyang Z, Lai C, Yang H, Li L, Liu Q, Shi H, Xu G, Zhao H, Wei H, Pei Z, Li S, Lai L, Li XJ. A Huntingtin Knockin Pig Model Recapitulates Features of Selective Neurodegeneration in Huntington's Disease. 2018 May 3;173(4):989-1002.e13.

2. Yan S, Zheng X, Lin Y, Li C, Liu Z, Li J, Tu Z, Zhao Y, Huang C, Chen Y, Li J, Song X, Han B, Wang W, Liang W, Lai L, Li XJ, Li S.Cas9-mediated replacement of expanded CAG repeats in a pig model of Huntington's disease. Nat Biomed Eng. 2023 May;7(5):629-646.

3. 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 Nov;10(31):e2301120.