Motor neuron disease-associated loss of nuclear TDP-43 is linked to DNA double-strand break repair defects

作者：Joy Mitra, Erika N. Guerrero, Pavana M. Hegde, Nicole F. Liachko, Haibo Wang, Velmarini Vasquez, Junling Gao, Arvind Pandey, J. Paul Taylor, Brian C. Kraemer, Ping Wu, István Boldogh, Ralph M. Garruto, Sankar Mitra, K. S. Rao, Muralidhar L. Hegde · 发表于：Proceedings of the National Academy of Sciences · 年份：2019 · DOI：10.1073/pnas.1818415116 · 被引用次数：324 · 研究领域：Amyotrophic Lateral Sclerosis Research、Neurogenetic and Muscular Disorders Research、Prion Diseases and Protein Misfolding

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.