Sun, Y., Dai, H., Dai, X., Yin, J., Cui, Y., Liu, X., Gonzalez, G., Yuan, J., Tang, F., Wang, N., Perlegos, A.E., Bonini, N.M., Yang, X.W., Gu, W., Wang, Y. (2023). m[1]A in CAG repeat RNA binds to TDP-43 and induces neurodegeneration.  Nature 623(7987): 580--587.

FBrf0258108

Research paper

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.

PMC10651481 (PMC) (EuropePMC)