VAPB is a highly conserved integral membrane protein that is ubiquitously expressed in all eukaryotic organisms and located within the membranes of the endoplasmic reticulum (ER) The P56S missense mutation of the VAPB protein is linked to a hereditary form of amyotrophic lateral sclerosis (ALS8), and the pathogenesis of ALS8 has remained enigmatic We report the cloning of five novel splice variants of the human VAPB gene, all of which are expressed at the mRNA level in the human nervous system When transfected into human HEK293 or SH-SY5Y cells, two of these variants (VAPB-2 and VAPB-4,5) were readily detectable by immunoblotting whereas two variants (VAPB-3 and VAPB-3,4) became detectable after proteasomal inhibition, a condition commonly found in neurodegenerative diseases Interestingly, one of these novel VAPB variants, VAPB-2, co-immunoprecipitated with wt-VAPB However, so far none of these splice variants could be detected by immunoblotting of lysates from selected human tissues, suggesting that in vim the proteins translated from the variant VAPB mRNAs are quickly degraded or, alternatively, the expressed proteins are below detection limit of the available antibodies We speculate that under conditions of proteasomal inhibition, as encountered in many neurodegenerative diseases including ALS, variant VAPB proteins might accumulate in affected cells and contribute to ALS pathogenesis (C) 2010 Elsevier Inc All rights reserved