Motor neuron disease-associated loss of nuclear TDP-43 is linked to DNA double-strand break repair defects
Open accessAbstract
Significance: Amyotrophic lateral sclerosis (ALS) is a devastating, motor neuron degenerative disease without any cure to date. About 95% of ALS patients feature abnormalities in the RNA/DNA binding protein TDP-43, involving its nucleus-cytoplasmic mislocalization in spinal motor neurons. How TDP-43 pathology triggers neuronal apoptosis remains unclear. Here, we report that TDP-43 participates in the DNA damage response and its nuclear clearance in motor neurons causes DNA double-strand break repair defects in ALS. Our findings uncover a link between TDP-43 pathology and impaired DNA repair, and suggest potential avenues for DNA repair-targeted therapies for TDP-43–ALS.
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TDP-43 is directly involved in NHEJ through its recruitment and stabilization of the XRCC4-LIG4 complex at DSBs.
“Recently, TDP‐43 was also found to be directly involved in NHEJ through its recruitment and stabilization of the XRCC4‐LIG4 complex at DSBs (Guerrero et al, 2019; Mitra et al, 2019).”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Mitra et al, 2019
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- Authors
- Mitra, J., Guerrero, E. N., Hegde, P. M., Liachko, N. F., Wang, H., Vasquez, V., Gao, J., Pandey, A., Taylor, J. P., Kraemer, B. C., Wu, P., Boldogh, I., Garruto, R. M., Mitra, S., Rao, K. S., & Hegde, M. L.
- Affiliations
- Houston Methodist (US)
- University of Washington (US)
- The University of Texas Medical Branch at Galveston (US)
- St. Jude Children's Research Hospital (US)
- Binghamton University (US)
- Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (PA)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2019-02-15
- Volume
- 116
- Issue
- 10
- Pages
- 4696-4705
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6410842
- OpenAlex
- W2807481171
- Cited by
- 305
- References
- 66
- Citations by year
- 2026: 25 · 2025: 41 · 2024: 45 · 2023: 40 · 2022: 48 · 2021: 52 · 2020: 33 · 2019: 21
- FWCI
- 26.06
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- SSRN Electronic Journal (acceptedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Health (R01 NS088645)
- Muscular Dystrophy Association (MDA294842)
- U.S. Department of Veterans Affairs (CDA2 BX007080, BX-003755)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- amyotrophic lateral sclerosis, TDP-43, motor neuron disease, DNA double-strand break repair, DNA damage response, motor neuron apoptosis
- MeSH terms
- Amyotrophic Lateral Sclerosis, Animals, DNA Repair, DNA-Binding Proteins, Humans, Motor Neurons, Protein Binding, RNA-Binding Proteins, Caenorhabditis elegans, Caenorhabditis elegans Proteins, DNA Breaks, Double-Stranded, DNA End-Joining Repair
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