Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 288, Issue 5, Pages 3641-3654Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.433615
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Funding
- Ministry for Education, Culture, and Sports, Science and Technology of Japan [23111006, 23110523, 22700404]
- Research Committee of CNS Degenerative Diseases
- Ministry of Health, Labour, and Welfare of Japan
- Takeda Science Foundation
- Naito Foundation
- Grants-in-Aid for Scientific Research [22700404] Funding Source: KAKEN
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Abnormal protein accumulation is a pathological hallmark of neurodegenerative diseases, including accumulation of TAR DNA-binding protein 43 (TDP-43) in amyotrophic lateral sclerosis (ALS). 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 not known. Here, we found that longer half-lives of mutant proteins correlated with accelerated disease onset. Based on our findings, we established a cell model in which chronic stabilization of wildtype TDP-43 protein provoked cytotoxicity and recapitulated pathogenic protein cleavage and insolubility to the detergent Sarkosyl, TDP-43 properties that have been observed in sporadic ALS lesions. Furthermore, these cells 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.
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