Lipid trafficking defects increase Beclin-1 and activate autophagy in Niemann-Pick type C disease

Niemann-Pick type C disease (NPC) is a sphingolipid storage disorder characterized by progressive neurodegeneration that typically shows juvenile onset. Mutations in the Npc1 gene cause similar to 95% of NPC cases. NPC1 is a multipass transmembrane protein involved in lipid and cholesterol trafficking. Loss of function mutations in Npc1 lead to the accumulation of sphingolipids and cholesterol in late endosomes and lysosomes. In our study, we demonstrated that NPC 1 deficiency results in increased basal autophagy in human fibroblasts and in mice. We further demonstrated that NPC1 deficiency activates basal autophagy through increased expression of Beclin-1, a highly conserved member of the class III PI3K complex that is critical for the formation of outophagosomes. In contrast, enhanced basal autophogy was not associated with activation of the Akt-mTOR-p70 S6K signaling pathway. Increased Beclin-1 levels and elevated autophagy were also observed in other sphingolipid storage diseases characterized by disrupted cholesterol and sphingolipid trafficking. We propose a model in which the disordered cholesterol trafficking that occurs in many sphingolipid storages diseases results in upregulation of Beclin-1 and enhanced levels of autophagy.