[Biochemical abnormality of mutant TDP-43 protein].

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.