title: [Biochemical abnormality of mutant TDP-43 protein].
abstract: Dominant mutations in the TDP-43 gene are causative for familial ALS, however, the relationship between mutant protein biochemical phenotypes and disease course and their significance to disease pathomechanism are unclarified. We found that longer half-lives of mutant proteins correlated with accelerated disease onset. Increased stability of TDP-43 protein was also observed in ALS/FTLD linked mutations in RNA recognition motif of TDP-43. Based on our findings, we established a cell model in which chronic stabilization of wild-type TDP-43 protein provoked cytotoxicity and recapitulated pathogenic protein cleavage and insolubility to the detergent sarkosyl, TDP-43 properties that have been observed in the lesions of sporadic ALS. Moreover, these cells expressing stabilized TDP-43 showed proteasomal impairment and dysregulation of their own mRNA levels. These results suggest that chronically increased stability of mutant or wild-type TDP-43 proteins results in a gain of toxicity through abnormal proteostasis.
authors.affiliation: Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University.
authors.forename: Koji
authors.initials: K
authors.lastname: Yamanaka
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000633:toxicity; D006801:Humans; D051379:Mice; D009154:Mutation; D055550:Protein Stability; D057165:Proteostasis Deficiencies / Q000235:genetics; D012333:RNA, Messenger
chemical_list: D004268:DNA-Binding Proteins; D012333:RNA, Messenger; C000598624:TARDBP protein, human