title: Amyotrophic lateral sclerosis-linked mutant VAPB enhances TDP-43-induced motor neuronal toxicity.
abstract: Transactive response DNA-binding protein-43 (TDP-43) has been thought to be generally involved in the pathogenesis of most amyotrophic lateral sclerosis (ALS) patients although it remains undefined how TDP-43 is involved in the ALS pathogenesis. In this study, we found that a P56S mutant of vesicle-associated membrane protein-associated protein B (VAPB), which has been identified to be a familial ALS-causative protein, potentiated the TDP-43-induced motor neuronal cell death, while wild-type VAPB conversely inhibited it. The P56S-VAPB-induced potentiation of the TDP-43-induced death was mediated by the up-regulation of Bim expression at the mRNA level and other undefined mechanisms that leads to the enhancement of Bim and Bax activity. These observations suggest that TDP-43 and P56S-VAPB may co-operate to involve the pathogenesis of ALS.
authors.affiliation: Department of Pharmacology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Suzuki
authors.forename: Masaaki
authors.initials: M
authors.lastname: Matsuoka
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D016923:Cell Death / Q000235:genetics; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000633:toxicity*; D006801:Humans; D006822:Hybrid Cells; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000473:pathology / Q000502:physiology*; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017354:Point Mutation / Q000235:genetics*; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; C496748:VAPB protein, human; D033921:Vesicular Transport Proteins