title: Accelerated disease onset with stabilized familial amyotrophic lateral sclerosis (ALS)-linked mutant TDP-43 proteins.
abstract: 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 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 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.
authors.affiliation: Laboratory for Motor Neuron Disease, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Watanabe
authors.forename: Kumi
authors.initials: K
authors.lastname: Kaneko
authors.forename: Koji
authors.initials: K
authors.lastname: Yamanaka
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D003902:Detergents / Q000494:pharmacology; D005091:Exons / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012995:Solubility; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
chemical_list: D004268:DNA-Binding Proteins; D003902:Detergents; D050505:Mutant Proteins; D012333:RNA, Messenger; D046988:Proteasome Endopeptidase Complex