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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.

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