M6A reduction relieves FUS-associated ALS granules

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease due to gradual motorneurons (MN) degeneration[1][1]. Among the processes associated to ALS pathogenesis, there is the formation of cytoplasmic inclusions produced by mutant protein aggregation, among which the RNA binding protein FUS[2][2]. In this work we show that such inclusions are significantly reduced in number and dissolve faster when the RNA m[6][3]A content is diminished as a consequence of the m[6][3]A writer METTL3 knock-down. These effects were observed both in neuronal cell lines and in iPSC-derived human motor neurons expressing mutant FUS. Importantly, stress granules formed in ALS condition showed a distinctive transcriptome with respect to control cells; interestingly, after METTL3 downregulation, it reverted to similar to control. Finally, we show that FUS inclusions are reduced also in patient-derived fibroblasts treated with STM-2457, a well characterized inhibitor of METTL3 activity, paving the way for its possible use for counteracting aggregate formation in ALS. ### Competing Interest Statement Sapienza University of Rome and Fondazione Istituto Italiano di Tecnologia (IIT) submitted a patent application. [1]: #ref-1 [2]: #ref-2 [3]: #ref-6