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Using a Drosophila model of TDP-43 pathology, we show that aberrant activity of m\n                    <jats:sup>5<\/jats:sup>\n                    C-RNA methyltransferases Nsun1 drives TDP-43\u2013induced m\n                    <jats:sup>5<\/jats:sup>\n                    C-RNA hypermethylation, whereas Nsun1 down-regulation alleviates TDP-43\u2013induced degeneration, lifespan deficits, and cytoplasmic accumulation. In human cells, TDP-43 selectively interacts with NSUN1 isoform 3 independently of RNA. Furthermore, NSUN1 is nucleolar and TDP-43 is largely nucleoplasmic, yet they interact in both compartments, suggesting functional roles beyond their predominant localisations. In ALS\/FTD postmortem frontal cortex, NSUN1 isoform 3 persists, whereas the shorter isoform is reduced, suggesting that a pool of NSUN1 capable of contributing to pathological TDP-43 interactions remains in disease. These findings suggest that TDP-43 neurotoxicity is coupled to NSUN1 activation and m\n                    <jats:sup>5<\/jats:sup>\n                    C-RNA methylation, revealing a potential therapeutic axis in ALS\/FTD.\n                  <\/jats:p>","DOI":"10.26508\/lsa.202503297","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T06:21:16Z","timestamp":1760682076000},"page":"e202503297","update-policy":"https:\/\/doi.org\/10.26508\/lsa.crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Aberrant NSUN1 activity connects m\n                    <sup>5<\/sup>\n                    C-RNA modification to TDP-43 neurotoxicity in 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