Amyotrophic Lateral Sclerosis Mutant VAPB Causes a Nuclear Envelope Defect

Abstract

A proline to serine substitution (P56S) in VAPB causes an autosomal dominant form of Amyotrophic Lateral Sclerosis (ALS). We show that the mutation also causes a nuclear envelope (NE) defect. Transport of Nucleoporins (Nups) and Emerin (EMD) to the NE is blocked, resulting in their sequestration in dilated cytoplasmic membranes. Simultaneous overexpression of the FFAT motif (two phenylalanines on an acidic track) antagonizes this mutant VAPB effect and restores transport to the NE. VAPB function is required for transport to the NE with knockdown of endogenous VAPB recapitulating this phenotype. Moreover, we identified this compartment as ER-Golgi intermediate compartment (ERGIC) with NE membrane proteins transiting to ERGIC before VAPB-dependent retrograde transport to the NE.