近日，美国加州大学欧文分校Leslie M. Thompson等研究人员合作发现，亨廷顿病中的剪接异常伴随着TDP-43活性失调和m6A RNA修饰的改变。相关论文于2025年1月6日在线发表在《自然—神经科学》杂志上。

研究人员发现TDP-43和N6-甲基腺苷（m6A）写入蛋白METTL3是多个亨廷顿病（HD）系统中外显子跳跃的上游调控因子。在HD小鼠和人类大脑中，TDP-43的核定位被破坏，磷酸化TDP-43在细胞质中积累，且TDP-43与HTT核聚集体样结构共同定位。

这些结构与突变型HTT包涵体不同。TDP-43与编码HD相关差异表达和异常剪接基因的RNA结合减少。最后，在HD R6/2小鼠大脑纹状体中，异常表达的RNA上的m6A修饰减少，尤其是在与TDP-43结合位点相邻的聚集区域。

这些证据支持TDP-43功能丧失与m6A修饰改变相结合，作为HD中替代剪接的机制。

研究人员表示，HD由HTT基因中的CAG重复扩展引起，导致基因表达改变。然而，导致HD中RNA处理紊乱的机制仍不清楚。

附：英文原文

Title: Aberrant splicing in Huntington’s disease accompanies disrupted TDP-43 activity and altered m6A RNA modification

Author: Nguyen, Thai B., Miramontes, Ricardo, Chillon-Marinas, Carlos, Maimon, Roy, Vazquez-Sanchez, Sonia, Lau, Alice L., McClure, Nicolette R., Wu, Zhuoxing, Wang, Keona Q., England, Whitney E., Singha, Monika, Stocksdale, Jennifer T., Heath, Marie, Jang, Ki-Hong, Jung, Sunhee, Ling, Karen, Jafar-nejad, Paymann, McKnight, Jharrayne I., Ho, Leanne N., Dalahmah, Osama Al, Faull, Richard L. M., Steffan, Joan S., Reidling, Jack C., Jang, Cholsoon, Lee, Gina, Cleveland, Don W., Lagier-Tourenne, Clotilde, Spitale, Robert C., Thompson, Leslie M.

Issue&Volume: 2025-01-06

Abstract: Huntington’s disease (HD) is caused by a CAG repeat expansion in the HTT gene, leading to altered gene expression. However, the mechanisms leading to disrupted RNA processing in HD remain unclear. Here we identify TDP-43 and the N6-methyladenosine (m6A) writer protein METTL3 to be upstream regulators of exon skipping in multiple HD systems. Disrupted nuclear localization of TDP-43 and cytoplasmic accumulation of phosphorylated TDP-43 occurs in HD mouse and human brains, with TDP-43 also co-localizing with HTT nuclear aggregate-like bodies distinct from mutant HTT inclusions. The binding of TDP-43 onto RNAs encoding HD-associated differentially expressed and aberrantly spliced genes is decreased. Finally, m6A RNA modification is reduced on RNAs abnormally expressed in the striatum of HD R6/2 mouse brain, including at clustered sites adjacent to TDP-43 binding sites. Our evidence supports TDP-43 loss of function coupled with altered m6A modification as a mechanism underlying alternative splicing in HD.

DOI: 10.1038/s41593-024-01850-w

Source: https://www.nature.com/articles/s41593-024-01850-w