Figure 7.

Model of the relationship between NPC1 deficiency, autophagy and tau. Functional deficiency of NPC1 impairs intracellular lipid trafficking and leads to the accumulation of unesterified cholesterol, sphingolipids and complex gangliosides in the late endosomal/lysosomal network. Pathological changes in NPC include progressive neurodegeneration associated with the accumulation of hyperphosphorylated tau (depicted at right). In NPC model systems and patient fibroblasts, defects in lipid transport stimulate a Beclin-1-dependent increase of basal autophagy, which we propose exerts a protective effect by facilitating the re-use of critical cellular components. The deletion of endogenous tau abrogates this response and exacerbates the NPC phenotype. We speculate that similar effects may be triggered by tau hyperphosphorylation, as occurs in NPC patients.