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J Neurochem. 2011 Dec;119(5):1099-107. doi: 10.1111/j.1471-4159.2011.07491.x. Epub 2011 Oct 20.

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

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Department of Pharmacology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, Japan.


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.

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