A mutation in ER membrane protein VAPB is responsible for causing a familial form of ALS (ALS8). The VAPB-P56S mutation causes protein aggregation and a nuclear envelope defect, where retrograde transport is disrupted. Over-expression of a FFAT peptide from OSBP1 reduces the size of VAPB-P56S aggregates and restores retrograde transport. A screen was performed on FFAT-motif containing ORPs to determine if any could rescue the mutant phenotype. ORP3 successfully reduced aggregate size and restored transport to the nuclear envelope. ER membrane protein Sac1, a PI4P phosphatase cycles between the ER and Golgi and becomes trapped in expanded ERGIC compartments with VAPB-P56S. Loss of Sac1 in the ER leads to an increase in intracellular PI4P. ORP3 may increase Sac1 phosphatase activity by acting as a lipid sensor. We propose that VAPB, Sac1 and ORP3 are interacting partners that together modulate levels of PI4P. Disruptions in the gradient of PI4P may result in the vesicle trafficking defects observed in VAPB-P56S cells.

A mutation in ER membrane protein VAPB is responsible for causing a familial form of ALS (ALS8). The VAPB-P56S mutation causes protein aggregation and a nuclear envelope defect, where retrograde transport is disrupted. Over-expression of a FFAT peptide from OSBP1 reduces the size of VAPB-P56S aggregates and restores retrograde transport. A screen was performed on FFAT-motif containing ORPs to determine if any could rescue the mutant phenotype. ORP3 successfully reduced aggregate size and restored transport to the nuclear envelope. ER membrane protein Sac1, a PI4P phosphatase cycles between the ER and Golgi and becomes trapped in expanded ERGIC compartments with VAPB-P56S. Loss of Sac1 in the ER leads to an increase in intracellular PI4P. ORP3 may increase Sac1 phosphatase activity by acting as a lipid sensor. We propose that VAPB, Sac1 and ORP3 are interacting partners that together modulate levels of PI4P. Disruptions in the gradient of PI4P may result in the vesicle trafficking defects observed in VAPB-P56S cells.

Amyotrophic Lateral Sclerosis (ALS) is a fatal, late-onset, progressive neurodegenerative disease. A familial form of ALS, autosomal dominant ALS8, is characterized by a mutation in an ER membrane protein, VAPB. To characterize the role of VAPB in motor neurons, two C. elegans models were generated: one expressing human VAPB-P56S and another with the knockdown of C. elegans VAPB ortholog, VPR-1. Overexpression of human VAPB in DA neurons caused backward locomotion defects, enhanced vulnerability to oxidative stress and premature neuronal death. Knockdown of vpr-1 in C. elegans recapitulated the loss of protein function believed to be associated with human cases of ALS8. It caused backward locomotion defects, such as uncoordination and slowed rates of movement, as well as age-dependent motor neuronal death. In both models, DA6 and DA7 were the most vulnerable motor neurons. Because of the unexpected developmental defects associated with the VAPB transgenic model, the knockdown of vpr-1 may be a better model to recapitulate the human disease. This model provides further support that ALS8 pathogenesis is due to a loss of VAPB protein function and can also be used to test drugs or treatments that may delay the onset of neuronal death.