Guangdong Key Laboratory of Non-human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China.
State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China.
Sci Adv. 2024 May 17;10(20):eadl2036. doi: 10.1126/sciadv.adl2036.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease characterized by preferential neuronal loss in the striatum. The mechanism underlying striatal selective neurodegeneration remains unclear, making it difficult to develop effective treatments for HD. In the brains of nonhuman primates, we examined the expression of Huntingtin (), the gene responsible for HD. We found that HTT protein is highly expressed in striatal neurons due to its slow degradation in the striatum. We also identified tripartite motif-containing 37 (TRIM37) as a primate-specific protein that interacts with HTT and is selectively reduced in the primate striatum. TRIM37 promotes the ubiquitination and degradation of mutant HTT (mHTT) in vitro and modulates mHTT aggregation in mouse and monkey brains. Our findings suggest that nonhuman primates are crucial for understanding the mechanisms of human diseases such as HD and support TRIM37 as a potential therapeutic target for treating HD.
亨廷顿病（HD）是一种常染色体显性神经退行性疾病，其特征是纹状体中神经元优先丢失。纹状体选择性神经退行性变的机制尚不清楚，因此难以开发针对 HD 的有效治疗方法。在非人类灵长类动物的大脑中，我们研究了负责 HD 的基因亨廷顿蛋白（）的表达。我们发现由于 HTT 在纹状体中的降解缓慢，HTT 蛋白在纹状体神经元中高度表达。我们还鉴定了三部分基序包含蛋白 37（TRIM37）作为一种灵长类特异性蛋白，与 HTT 相互作用，并在灵长类纹状体中选择性减少。TRIM37 促进体外突变型 HTT（mHTT）的泛素化和降解，并调节小鼠和猴子大脑中 mHTT 的聚集。我们的研究结果表明，非人类灵长类动物对于理解亨廷顿病等人类疾病的机制至关重要，并支持 TRIM37 作为治疗 HD 的潜在治疗靶点。
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