Abstract
The tauopathies are a diverse class of devastating neurodegenerative disorders, characterized by the hyperphosphorylation and aggregation of the microtubule binding protein tau. Niemann-Pick type C disease (NPC) is a tauopathy that affects children,and is caused by mutations in intracellular lipid and cholesterol trafficking proteins. Loss-of-function mutations in the NPC1gene are responsible for 95 percent of all NPC cases, and lead to progressive neurodegeneration and early death. To assess the extent to which tau affects NPC pathology, we generated mice that lack both NPC1 and tau. NPC1/tau double-null mutants exhibit an exacerbated NPC phenotype, including severe systemic manifestations,and die significantly earlier than NPC1 single-null mutants.Since autophagy has been previously implicated in NPC pathogenesis,we investigated the impact of tau deletion on this pathway.Acute reductions of tau in NPC1-deficient fibroblasts significantly decrease autophagic induction and flux, while having no effect on the autophagic pathway in control cells. Here we propose a model in which tau's normal function is critical to the induction of autophagy in NPC1 deficiency, and suggest that this novel mechanism contributes to cellular dysfunction in the tauopathies.