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

Yuxiang Sun, 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 and Yinsheng Wang ()
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Yuxiang Sun: University of California Riverside
Hui Dai: University of California Riverside
Xiaoxia Dai: University of California Riverside
Jiekai Yin: University of California Riverside
Yuxiang Cui: University of California Riverside
Xiaochuan Liu: University of California Riverside
Gwendolyn Gonzalez: University of California Riverside
Jun Yuan: University of California Riverside
Feng Tang: University of California Riverside
Nan Wang: University of California Los Angeles
Alexandra E. Perlegos: University of Pennsylvania
Nancy M. Bonini: University of Pennsylvania
X. William Yang: University of California Los Angeles
Weifeng Gu: University of California Riverside
Yinsheng Wang: University of California Riverside

Nature, 2023, vol. 623, issue 7987, 580-587

Abstract: 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 N1-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.

Date: 2023
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DOI: 10.1038/s41586-023-06701-5

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