VAMP associated proteins are required for autophagic and lysosomal degradation by promoting a PtdIns4P-mediated endosomal pathway.

ABSTRACT

Mutations in the ER-associated VAPB/ALS8 protein cause amyotrophic lateral sclerosis and spinal muscular atrophy. Previous studies have argued that ER stress may underlie the demise of neurons. We find that loss of VAP proteins (VAPs) leads to an accumulation of aberrant lysosomes and impairs lysosomal degradation. VAPs mediate ER to Golgi tethering and their loss may affect phosphatidylinositol-4-phosphate (PtdIns4P) transfer between these organelles. We found that loss of VAPs elevates PtdIns4P levels in the Golgi, leading to an expansion of the endosomal pool derived from the Golgi. Fusion of these endosomes with lysosomes leads to an increase in lysosomes with aberrant acidity, contents, and shape. Importantly, reducing PtdIns4P levels with a PtdIns4-kinase (PtdIns4K) inhibitor, or removing a single copy of Rab7, suppress macroautophagic/autophagic degradation defects as well as behavioral defects observed in Drosophila Vap33 mutant larvae. We propose that a failure to tether the ER to the Golgi when VAPs are lost leads to an increase in Golgi PtdIns4P levels, and an expansion of endosomes resulting in an accumulation of dysfunctional lysosomes and a failure in proper autophagic lysosomal degradation. Abbreviations ALS amyotrophic lateral sclerosis; CSF cerebrospinal fluid; CERT ceramide transfer protein; FFAT two phenylalanines in an acidic tract; MSP major sperm proteins; OSBP oxysterol binding protein; PH pleckstrin homology; PtdIns4P phosphatidylinositol-4-phosphate; PtdIns4K phosphatidylinositol 4-kinase; UPR unfolded protein response; VAMP vesicle-associated membrane protein; VAPA/B mammalian VAPA and VAPB proteins; VAPs VAMP-associated proteins (referring to Drosophila Vap33, and human VAPA and VAPB).