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MA reduction relieves FUS-associated ALS granules. | LitMetric

AI Article Synopsis

  • Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by the gradual degeneration of motoneurons, leading to impaired muscle function.
  • Research indicates that reducing RNA mA levels in neuronal cells can significantly decrease the number of cytoplasmic inclusions formed by mutant proteins like FUS, which are associated with ALS.
  • Treatment with STM-2457, an inhibitor of METTL3, not only reduces FUS inclusions in patient-derived fibroblasts but also highlights the potential for targeting mA homeostasis to combat aggregate formation in ALS.

Article Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease due to gradual motoneurons (MN) degeneration. Among the processes associated to ALS pathogenesis, there is the formation of cytoplasmic inclusions produced by aggregation of mutant proteins, among which the RNA binding protein FUS. Here we show that, in neuronal cells and in iPSC-derived MN expressing mutant FUS, such inclusions are significantly reduced in number and dissolve faster when the RNA mA content is diminished. Interestingly, stress granules formed in ALS conditions showed a distinctive transcriptome with respect to control cells, which reverted to similar to control after mA downregulation. Notably, cells expressing mutant FUS were characterized by higher mA levels suggesting a possible link between mA homeostasis and pathological aggregates. Finally, we show that FUS inclusions are reduced also in patient-derived fibroblasts treated with STM-2457, an inhibitor of METTL3 activity, paving the way for its possible use for counteracting aggregate formation in ALS.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11169559PMC
http://dx.doi.org/10.1038/s41467-024-49416-5DOI Listing

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