title: TDP-43 identified from a genome wide RNAi screen for SOD1 regulators.
abstract: Amyotrophic Lateral Sclerosis (ALS) is a late-onset, progressive neurodegenerative disease affecting motor neurons in the brain stem and spinal cord leading to loss of voluntary muscular function and ultimately, death due to respiratory failure. A subset of ALS cases are familial and associated with mutations in superoxide dismutase 1 (SOD1) that destabilize the protein and predispose it to aggregation. In spite of the fact that sporadic and familial forms of ALS share many common patho-physiological features, the mechanistic relationship between SOD1-associated and sporadic forms of the disease if any, is not well understood. To better understand any molecular connections, a cell-based protein folding assay was employed to screen a whole genome RNAi library for genes that regulate levels of soluble SOD1. Statistically significant hits that modulate SOD1 levels, when analyzed by pathway analysis revealed a highly ranked network containing TAR DNA binging protein (TDP-43), a major component of aggregates characteristic of sporadic ALS. Biochemical experiments confirmed the action of TDP-43 on SOD1. These results highlight an unexpected relationship between TDP-43 and SOD1 which may have implications in disease pathogenesis.
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America. balajee.somalinga@utsouthwestern.edu
authors.forename: Balajee R
authors.initials: BR
authors.lastname: Somalinga
authors.forename: Cameron E
authors.initials: CE
authors.lastname: Day
authors.forename: Shuguang
authors.initials: S
authors.lastname: Wei
authors.forename: Michael G
authors.initials: MG
authors.lastname: Roth
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Thomas
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016678:Genome; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000737:chemistry / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
chemical_list: D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1