Expression of VAPB cleavage of products in peripheral blood leukocytes and cerebrospinal fluid of patients with sporadic amyotrophic lateral sclerosis

Background and purpose: Vesicle-associated membrane-protein-associated protein B(VAPB) is an endoplasmic reticulum (ER) resident protein participating in ER func-tion, vesicle trafficking, calcium homeostasis and lipid transport. Its N-terminaldomain, named MSP, is cleaved and secreted, serving as an extracellular ligand.VAPB mutations are linked to autosomal-dominant motor neuron diseases, includ-ing amyotrophic lateral sclerosis (ALS) type 8. An altered VAPB function is alsosuspected in sporadic ALS (SALS).Methods: The expression pattern of VAPB cleavage and secreted products in theperipheral blood leukocytes (PBL) and cerebrospinal fluid (CSF) of SALS patientsand neurological controls was assessed. PBL from healthy controls were alsoanalyzed. Assays were carried out through western blotting, using an anti-VAPB(N-terminal) antibody.Results: Two VAPB fragments containing the MSP domain (17 kDa and 14 kDamolecular sizes) were identified in PBL of SALS and controls, with no significantdifferences amongst groups. In CSF, only the 14 kDa VAPB MSP fragment wasexpressed and a corresponding VAPA fragment was not detected. The CSF VAPBfragment was absent in 58.7% of SALS patients, of whom 79.2% were bulbar onset(P = 0.001, bulbar versus spinal).Conclusions: The absence of the CSF VAPB MSP fragment from most bulbar-onset SALS patients suggests a specific alteration of brain-derived VAPB cleavageand secretion in this group of patients, and hints at a role of VAPB in the patho-physiology of this motor neuron disease