# FUS is an N1- and N6-methyladenosine-binding protein

## TL;DR

This study shows that the FUS protein binds to specific RNA modifications, which may contribute to neurological diseases like ALS and FTLD.

## Contribution

The discovery that FUS binds to N1- and N6-methyladenosine in RNA provides a novel mechanism for FUS-related neurodegeneration.

## Key findings

- FUS binds to methylated adenosines in CAG repeat RNA, causing cytoplasmic redistribution.
- Reducing m1A and m6A levels decreases FUS-RNA co-localization in cells.
- Binding to methylated RNA makes FUS less mobile in the cytosol.

## Abstract

Nucleotide repeat expansions contribute to a number of neurological disorders. Mutations and augmented expression in fused in sarcoma (FUS) can result in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here we reveal that FUS is an N1- and N6-methyladenosine (m1A- and m6A)-binding protein, where the protein interacts with the methylated adenosines in CAG repeat expansion RNA, thereby leading to the protein’s cytoplasmic redistribution in SH-SY5Y cells. We also found that ectopically expressed FUS co-localizes with CAG repeat RNA in the cytosol. This co-localization is diminished upon genetic depletion of m6A and m1A writer proteins (i.e. METTL3 and TRMT61A), pharmacological inhibition of METTL3, and ectopic overexpression of m1A and m6A eraser proteins (i.e. ALKBH3 and FTO). Moreover, binding to methylated CAG repeat RNA renders the ectopically expressed FUS protein less dynamic in cells. Together, our study underscores a critical role for m1A and m6A in enhancing FUS–RNA interaction, which results in aberrant subcellular distribution and attenuated mobility of the protein in cells. These findings unveil a novel mechanism underlying neurodegenerative disorders emanating from elevated expression of FUS and suggest targeting FUS-methylated adenosine interactions as a potential therapeutic strategy for FUS proteinopathy.

Graphical Abstract