Amyotrophic lateral sclerosis‐linked mutant VAPB enhances TDP‐43‐induced motor neuronal toxicity

J. Neurochem. (2011) 119 , 1099–1107. 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.