Autophagic Dysfunction in Gaucher Disease and its Rescue by Cathepsin B and D Proteases

Gaucher disease is a lysosomal storage disorder generally due to defective function of the enzyme glucosylceramidase, which catalyzes glucosylceramide hydrolysis in the presence of its activator, saposin C. A rare variant form of Gaucher disease, saposin C deficiency, is caused by mutations in the prosaposin ( PSAP ) gene that affect saposin C expression or function. Saposin C deficiency is characterized by the accumulation of undegraded macromolecules in lysosomes, which become large and dysfunctional. The reduced function of lysosomes leads to altered autophagy, which is emerging as a common event in the pathogenesis of neurodegenerative lysosomal storage diseases. Studies on primary fibroblasts from saposin C deficiency patients documented that mutations involving one cysteine residue result in a complete lack of the protein and consequent autophagic dysfunction. By different technical approaches, we demonstrated that the accumulation of autophagosomes, observed in saposin C-deficient fibroblasts, is derived from delayed autolysosome degradation, partially caused by decreased amounts and reduced enzymatic activities of cathepsins B and D. On the contrary, neither reduction of cathepsins nor autophagic disturbance was present in glucosylceramidase-deficient fibroblasts. Transient overexpression of cathepsin B and cathepsin D in saposin C-deficient cells was found to improve the degradation of autolysosomes and almost totally restore the autophagic flux and lysosome homeostasis. These findings highlight a novel mechanism altering autophagy in neurodegenerative lysosomal storage disorders.