RNA methylation influences TDP43 binding and disease pathogenesis in models of amyotrophic lateral sclerosis and frontotemporal dementia

• Published in: Molecular cell Vol. 83; no. 2; pp. 219 - 236.e7
• Main Authors: McMillan, Michael, Gomez, Nicolas, Hsieh, Caroline, Bekier, Michael, Li, Xingli, Miguez, Roberto, Tank, Elizabeth M.H., Barmada, Sami J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.01.2023
• Subjects: ALS; Amyotrophic Lateral Sclerosis - pathology; Frontotemporal Dementia - genetics; Frontotemporal Dementia - metabolism; Humans; m6A; Methylation; neurodegeneration; Neurons - metabolism; RNA - genetics; RNA - metabolism; RNA modifications; TDP43; TDP43; ALS; neurodegeneration; m6A; methylation; RNA modifications
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2022.12.019

RNA methylation at adenosine N6 (m6A) is one of the most common RNA modifications, impacting RNA stability, transport, and translation. Previous studies uncovered RNA destabilization in amyotrophic lateral sclerosis (ALS) models in association with accumulation of the RNA-binding protein TDP43. Here, we show that TDP43 recognizes m6A RNA and that RNA methylation is critical for both TDP43 binding and autoregulation. We also observed extensive RNA hypermethylation in ALS spinal cord, corresponding to methylated TDP43 substrates. Emphasizing the importance of m6A for TDP43 binding and function, we identified several m6A factors that enhance or suppress TDP43-mediated toxicity via single-cell CRISPR-Cas9 in primary neurons. The most promising modifier—the canonical m6A reader YTHDF2—accumulated within ALS spinal neurons, and its knockdown prolonged the survival of human neurons carrying ALS-associated mutations. Collectively, these data show that m6A modifications modulate RNA binding by TDP43 and that m6A is pivotal for TDP43-related neurodegeneration in ALS. [Display omitted] •The RNA-binding protein TDP43 preferentially binds N6-methyladenosine (m6A)-modified RNA•Post-mortem samples from ALS patients display widespread RNA hypermethylation•Methylated RNA overlaps with TDP43 pathology in ALS patient spinal cord•Reduction of the m6A reader YTHDF2 mitigates TDP43-mediated toxicity in ALS models Mislocalization of the essential RNA-binding protein TDP43 is characteristic of ALS. McMillan and Gomez et al. show that RNA binding by TDP43 is strongly influenced by RNA methylation at adenosine N6 (m6A). They also uncover marked RNA hypermethylation in ALS and connect TDP43-mediated toxicity with the m6A reader YTHDF2.