m1A in CAG repeat RNA binds to TDP-43 and induces neurodegeneration

Research output: Journal Publications and ReviewsRGC 21 - Publication in refereed journalpeer-review

30 Scopus Citations
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Author(s)

  • Hui Dai
  • Xiaoxia Dai
  • Jiekai Yin
  • Yuxiang Cui
  • Xiaochuan Liu
  • Gwendolyn Gonzalez
  • Jun Yuan
  • Feng Tang
  • Nan Wang
  • Alexandra E. Perlegos
  • Nancy M. Bonini
  • X. William Yang
  • Weifeng Gu
  • Yinsheng Wang

Detail(s)

Original languageEnglish
Pages (from-to)580-587
Journal / PublicationNature
Volume623
Issue number7987
Online published8 Nov 2023
Publication statusPublished - 16 Nov 2023
Externally publishedYes

Link(s)

Abstract

Microsatellite repeat expansions within genes contribute to a number of neurological diseases1,2. The accumulation of toxic proteins and RNA molecules with repetitive sequences, and/or sequestration of RNA-binding proteins by RNA molecules containing expanded repeats are thought to be important contributors to disease aetiology3–9. Here we reveal that the adenosine in CAG repeat RNA can be methylated to N 1-methyladenosine (m1A) by TRMT61A, and that m1A can be demethylated by ALKBH3. We also observed that the m1A/adenosine ratio in CAG repeat RNA increases with repeat length, which is attributed to diminished expression of ALKBH3 elicited by the repeat RNA. Additionally, TDP-43 binds directly and strongly with m1A in RNA, which stimulates the cytoplasmic mis-localization and formation of gel-like aggregates of TDP-43, resembling the observations made for the protein in neurological diseases. Moreover, m1A in CAG repeat RNA contributes to CAG repeat expansion-induced neurodegeneration in Caenorhabditis elegans and Drosophila. In sum, our study offers a new paradigm of the mechanism through which nucleotide repeat expansion contributes to neurological diseases and reveals a novel pathological function of m1A in RNA. These findings may provide an important mechanistic basis for therapeutic intervention in neurodegenerative diseases emanating from CAG repeat expansion. © 2023, The Author(s).

Research Area(s)

Citation Format(s)

m1A in CAG repeat RNA binds to TDP-43 and induces neurodegeneration. / Sun, Yuxiang; Dai, Hui; Dai, Xiaoxia et al.
In: Nature, Vol. 623, No. 7987, 16.11.2023, p. 580-587.

Research output: Journal Publications and ReviewsRGC 21 - Publication in refereed journalpeer-review

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