亨廷顿蛋白
外显子
RNA剪接
生物
核糖核酸
亨廷顿病
RNA结合蛋白
亨廷顿蛋白
选择性拼接
分子生物学
基因
外显子跳跃
细胞生物学
突变体
遗传学
医学
内科学
疾病
作者
Thai B. Nguyen,Ricardo Miramontes,Carlos Chillón-Marinas,Roy Maimon,Sonia Vazquez‐Sanchez,Alice Lau,Nicolette McClure,Whitney England,Monika Singha,Jennifer Stocksdale,Ki-Hong Jang,Sunhee Jung,John McKnight,Leanne N. Ho,Richard L.M. Faull,Joan S. Steffan,Jack C. Reidling,Cholsoon Jang,Gina Lee,Don W. Cleveland,Clotilde Lagier‐Tourenne,Robert C. Spitale,Leslie Thompson
标识
DOI:10.1101/2023.10.31.565004
摘要
Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the first exon of the HTT gene encoding huntingtin. Prior reports have established a correlation between CAG expanded HTT and altered gene expression. However, the mechanisms leading to disruption of RNA processing in HD remain unclear. Here, our analysis of the reported HTT protein interactome identifies interactions with known RNA-binding proteins (RBPs). Total, long-read sequencing and targeted RASL-seq of RNAs from cortex and striatum of the HD mouse model R6/2 reveals increased exon skipping which is confirmed in Q150 and Q175 knock-in mice and in HD human brain. We identify the RBP TDP-43 and the N6-methyladenosine (m6A) writer protein methyltransferase 3 (METTL3) to be upstream regulators of exon skipping in HD. Along with this novel mechanistic insight, we observe decreased nuclear localization of TDP-43 and cytoplasmic accumulation of phosphorylated TDP-43 in HD mice and human brain. In addition, TDP-43 co-localizes with HTT in human HD brain forming novel nuclear aggregate-like bodies distinct from mutant HTT inclusions or previously observed TDP-43 pathologies. 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 striatum from 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 novel mechanism underlying alternative splicing/unannotated exon usage in HD and highlights the critical nature of TDP-43 function across multiple neurodegenerative diseases.
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