RNA methylation influences TDP43 binding and disease pathogenesis in models of amyotrophic lateral sclerosis and frontotemporal dementia
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Abstract
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.
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Other groups have observed that m6A accumulates in models of tauopathy, as well as in other diseases with intracellular aggregates, including ALS and Huntington's disease.
“Other groups have also observed that m6A accumulates in models of tauopathy, as well as in other diseases with intracellular aggregates, including ALS and Huntington’s disease (McMillan et al., 2023; Nguyen et al., 2023; Atrian et al., 2024).”
From β-amyloid accumulation enhances microtubule associated protein tau pathology in an APPNL-G-F/MAPTP301S mouse model of Alzheimer’s disease (2024) · cites this paper as McMillan et al., 2023
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- Authors
- McMillan, M., Gomez, N., Hsieh, C., Bekier, M., Li, X., Miguez, R., Tank, E. M. H., & Barmada, S. J.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Barmada, Sami J.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2023-01
- Volume
- 83
- Issue
- 2
- Pages
- 219-236.e7
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC9899051
- OpenAlex
- W4315928462
- Cited by
- 112
- References
- 108
- Citations by year
- 2026: 31 · 2025: 34 · 2024: 32 · 2023: 15
- FWCI
- 18.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 383 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Molecular Cell (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Michigan (P30AG072931, UL1TR000433)
- A. Alfred Taubman Medical Research Institute
- National Institutes of Health (1r56ns128110-01, UL1TR000433, CA04659229, P30CA04659229)
- Michigan Institute for Clinical and Health Research (MICHR, UL1TR000433, UL1TR000433)
- Rogel Cancer Center, University of Michigan
- National Institute on Aging (R21AG075368, P30AG072931)
- National Cancer Institute (P30CA046592)
- National Institute of General Medical Sciences (T32GM007863, T32GM145470)
- National Institute of Neurological Disorders and Stroke (R56 NS128110, R01NS113943, R01NS097542)
- National Center for Advancing Translational Sciences
- Robert Packard Center for ALS Research, Johns Hopkins University
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- RNA methylation, N6-methyladenosine, TDP-43, amyotrophic lateral sclerosis, frontotemporal dementia, YTHDF2, RNA-binding proteins, RNA destabilization, neurodegeneration, spinal cord neurons
- MeSH terms
- Amyotrophic Lateral Sclerosis, DNA-Binding Proteins, Humans, Methylation, Neurons, RNA, Frontotemporal Dementia
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