CLEAVAGE OF VAMP-ASSOCIATED PROTEINS (VAPs): A DIFFERENTIAL IMPLICATION IN SPORADIC AMYOTROPHIC LATERAL SCLEROSIS.

VAPs proteins, including VAPA and VAPB, are vesicle-associated membrane protein (VAMP)-associated proteins involved in the regulation of lipid transport, ER morphology and membrane trafficking. They contain an N-terminal domain, named MSP for the homology with the nematode major sperm protein, which is cleaved and secreted through unknown mechanism. MSP acts as an extracellular signal and likely regulates motor neuron survival and muscle function. Mutation at the VAPB-MSP (VAPB-P56S) is known to cause a familial amyotrophic lateral sclerosis (ALS8). No VAPA mutation is linked to ALS phenotype and VAPB-P56S protein does not undergo proteolysis. As spinal cord levels of VAPB are seen to be affected in sporadic ALS (SALS) patients and sod1 mutant mice, we here investigated the expression pattern of VAPs cleaved products in peripheral blood leukocytes (PBL) and cerebrospinal fluid (CSF) of SALS patients (n=46) and neurological controls (NC, n=33), throughout Western blotting using anti-VAPB and -VAPA antibodies. We found that VAPA and VAPB cleavage products differed. In CSF, VAPA cleavage products were never detected, whilst a 14 kDa band corresponding to VAPB-MSP was expressed. This CSF VAPB-MSP was absent in 58.7% of SALS patients of which 79.2% were bulbar-onset (p=0.001). We conclude that the absence of the CSF VAPB-MSP from most bulbar-onset SALS patients is a specific alteration of brain-derived VAPB cleavage/secretion in these patients and the identification of the protease responsible for the cleavage is crucial for defining the role of VAPB in the pathophysiology of this motor neuron disease.