Aberrant NSUN1 Activity Connects m5C RNA Modification to TDP-43 Neurotoxicity in ALS/FTD

TY - JOUR

T1 - Aberrant NSUN1 Activity Connects m5C RNA Modification to TDP-43 Neurotoxicity in ALS/FTD

AU - Parra-Torres, Melissa

AU - Dissanayake, Kumara

AU - Gray, James A.

AU - Langlands, Alistair J

AU - Kucuk, Ridvan

AU - Gierlinski, Marek

AU - Troakes, Claire

AU - King, Andrew

AU - McGurk, Leeanne

N1 - Publisher Copyright: © 2025 Parra-Torres et al.

PY - 2026/1

Y1 - 2026/1

N2 - In amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), the nuclear RNA-binding protein TDP-43 mislocalises to the cytoplasm and forms insoluble aggregates, but the mechanisms controlling this remain unclear. We define a native TDP-43 interactome in human SH-SY5Y cells and identify proteins linked to the 5-methylcytosine (m5C) RNA modification as highly enriched. Using a Drosophila model of TDP-43 pathology, we show that aberrant activity of m5C-RNA methyltransferases Nsun1 drives TDP-43-induced m5C-RNA hypermethylation, whereas Nsun1 down-regulation alleviates TDP-43-induced 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 m5C-RNA methylation, revealing a potential therapeutic axis in ALS/FTD.

AB - In amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), the nuclear RNA-binding protein TDP-43 mislocalises to the cytoplasm and forms insoluble aggregates, but the mechanisms controlling this remain unclear. We define a native TDP-43 interactome in human SH-SY5Y cells and identify proteins linked to the 5-methylcytosine (m5C) RNA modification as highly enriched. Using a Drosophila model of TDP-43 pathology, we show that aberrant activity of m5C-RNA methyltransferases Nsun1 drives TDP-43-induced m5C-RNA hypermethylation, whereas Nsun1 down-regulation alleviates TDP-43-induced 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 m5C-RNA methylation, revealing a potential therapeutic axis in ALS/FTD.

UR - https://www.scopus.com/pages/publications/105020894460

U2 - 10.26508/lsa.202503297

DO - 10.26508/lsa.202503297

M3 - Article

C2 - 41188020

SN - 2575-1077

VL - 9

JO - Life Science Alliance

JF - Life Science Alliance

IS - 1

M1 - e202503297

ER -