The ALS8-associated mutant VAPB^P56Sis resistant to proteolysis in neurons 

VAMP/synaptobrevin associated proteins A and B (VAPA and VAPB), are type IV membrane proteins enriched on ER and Golgi membranes. Both VAPA and B interact with cytoplasmic lipid transport proteins and cytoskeletal elements to maintain the structure and composition of ER and Golgi membranes. Truncated forms of both proteins are present in some tissues but the functional significance of this is not clear. In rodents processing of VAPA occurs in most tissues, however, truncated forms of VAPB have only been reported in brain tissue. It is demonstrated here that the extent of VAPB processing in rat increases during postnatal development and that it is restricted to neurons. The C-terminal polypeptide generated by this cleavage reaction remains associated with cell membranes, but its subcellular distribution is distinct from the full-length protein. A mutant form of VAPB is associated with a familial form of neurodegenerative disease, amyotrophic lateral sclerosis type 8. The mutant protein, VAPB<sup style="margin: 0px; padding: 0px; border: 0px; outline: 0px; font-size: 0.8em; vertical-align: super; background-color: rgb(255, 255, 255); line-height: 0.7em; white-space: nowrap; color: rgb(0, 0, 0); font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; orphans: auto; text-align: start; text-indent: 0px; text-transform: none; widows: auto; word-spacing: 0px; -webkit-text-stroke-width: 0px; background-position: initial initial; background-repeat: initial initial;">P56S</sup>, is resistant to truncation in primary neuronal cultures, although remains sensitive to some form of proteolysis when over-expressed in HEK293 cells. These data suggest that neuronal cells have a particular requirement for VAPB proteolysis and that reduced levels of processed polypeptides may contribute to the neurodegeneration associated with amyotrophic lateral sclerosis type 8.