SVIP is a molecular determinant of lysosomal dynamic stability, neurodegeneration and lifespan

Missense mutations in Valosin-Containing Protein ( VCP ) are linked to diverse degenerative diseases including IBMPFD, amyotrophic lateral sclerosis (ALS), muscular dystrophy and Parkinson’s disease. Here, we characterize a VCP-binding co-factor (SVIP) that specifically recruits VCP to lysosomes. SVIP is essential for lysosomal dynamic stability and autophagosomal–lysosomal fusion. SVIP mutations cause muscle wasting and neuromuscular degeneration while muscle-specific SVIP over-expression increases lysosomal abundance and is sufficient to extend lifespan in a context, stress-dependent manner. We also establish multiple links between SVIP and VCP -dependent disease in our Drosophila model system. A biochemical screen identifies a disease-causing VCP mutation that prevents SVIP binding. Conversely, over-expression of an SVIP mutation that prevents VCP binding is deleterious. Finally, we identify a human SVIP mutation and confirm the pathogenicity of this mutation in our Drosophila model. We propose a model for VCP disease based on the differential, co-factor-dependent recruitment of VCP to intracellular organelles. Valosin-Containing Protein (VCP) is linked to diverse degenerative diseases. Here, the authors show that Small VCP Interacting Protein (SVIP) recruits VCP to lysosomes, with gain and loss of SVIP muscle expression modifying neural degeneration, animal behaviour and lifespan.