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

2023; Nature Portfolio; Volume: 623; Issue: 7987 Linguagem: Inglês

10.1038/s41586-023-06701-5

1476-4687

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

RNA regulation and disease

Abstract Microsatellite repeat expansions within genes contribute to a number of neurological diseases 1,2 . 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 aetiology 3–9 . Here we reveal that the adenosine in CAG repeat RNA can be methylated to N 1 -methyladenosine (m 1 A) by TRMT61A, and that m 1 A can be demethylated by ALKBH3. We also observed that the m 1 A/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 m 1 A 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, m 1 A 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 m 1 A in RNA. These findings may provide an important mechanistic basis for therapeutic intervention in neurodegenerative diseases emanating from CAG repeat expansion.