M⁶A reduction relieves FUS-associated ALS granules

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease due to gradual motorneurons (MN) degeneration1. 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 FUS2. In this work we show that such inclusions are significantly reduced in number and dissolve faster when the RNA m6A content is diminished as a consequence of the m6A 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.

ALS-associated FUS mutation reshapes the RNA and protein composition of Stress Granules

“…This is of interest since both GAIN and LOSS transcripts could be both affected by the presence of mutant FUS in the cytoplasm. On one hand, the GAIN group RNAs are entrapped in granules that are more resistant to dissolution, and would suffer for the inability of FUS P525L SG to be promptly dissolved upon stress release 38,39 and to rapidly recover translational. On the other hand, the LOSS group RNAs would not be protected from stress-related damage since excluded from SG 56 .…”

“…2I and 2J). This is quite an interesting finding since both sets of transcripts can be equally vulnerable in the presence of mutant FUS: the GAIN group would suffer for the inability of FUS P525L SG to be promptly dissolved upon stress release 38,39 and would have a delayed translational recovery, while the LOSS one would not be protected from stress insults since excluded from SG. Altogether, these data suggest that the ALS-associated FUS P525L mutation has a strong effect on SG dynamics and induces a dramatic reorganization of the SG transcriptome which includes components previously associated to neuronal degeneration.…”