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<p>Huntington’s disease (HD) is caused by a CAG repeat expansion in the <i>HTT</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月6日

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

摘要

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.