Motor neuron disease-associated loss of nuclear TDP-43 is linked to DNA double-strand break repair defects
-
- Joy Mitra
- Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX 77030;
-
- Erika N. Guerrero
- Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX 77030;
-
- Pavana M. Hegde
- Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX 77030;
-
- Nicole F. Liachko
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108;
-
- Haibo Wang
- Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX 77030;
-
- Velmarini Vasquez
- Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX 77030;
-
- Junling Gao
- Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555;
-
- Arvind Pandey
- Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX 77030;
-
- J. Paul Taylor
- Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105;
-
- Brian C. Kraemer
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108;
-
- Ping Wu
- Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555;
-
- Istvan Boldogh
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555;
-
- Ralph M. Garruto
- Department of Anthropology, Binghamton University, State University of New York, Binghamton, NY 13902;
-
- Sankar Mitra
- Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX 77030;
-
- K. S. Rao
- Center for Neuroscience, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología, City of Knowledge, Panama, Republic of Panama;
-
- Muralidhar L. Hegde
- Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX 77030;
説明
<jats:title>Significance</jats:title><jats:p>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.</jats:p>
収録刊行物
-
- Proceedings of the National Academy of Sciences
-
Proceedings of the National Academy of Sciences 116 (10), 4696-4705, 2019-02-15
Proceedings of the National Academy of Sciences
