Disease modifying pathways in Niemann-Pick type C disease

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DESCRIPTION (provided by applicant): Niemann-Pick C disease is an autosomal recessive neurodegenerative disorder of childhood for which there is currently no effective treatment. This disorder results from deficiency of the intracellular cholesterol trafficking proteins NPC1 or NPC2, leading to the accumulation of cholesterol and glycolipids in late endosomes and lysosomes. How this cellular defect leads to neurodegeneration remains largely unknown. Processes compensating for pathologic lipid storage to promote neuronal survival represent promising therapeutic targets; however these are likewise not well understood. The objective of this application, therefore, is to identify cellular pathways that modulate the severity of neurodegeneration in Niemann-Pick C disease. This application is guided by preliminary data demonstrating that autophagy, a bulk degradation pathway for cytoplasmic proteins and organelles, is up-regulated in Niemann-Pick C disease. Additionally, our data demonstrate that deletion of the microtubule-associated protein tau markedly increases phenotypic severity of the Niemann-Pick C mouse model and impairs autophagy in NPC1-deficient cells. My central hypothesis is that the induction of autophagy and the presence of tau pathology are modifying factors in the pathogenesis of Niemann-Pick C disease. In my first Aim, I will establish the role of autophagy in modulating the severity of Niemann-Pick C disease, and evaluate autophagy as a therapeutic target. This will be accomplished by genetically inhibiting and pharmacologically enhancing autophagy in Niemann-Pick C mice, and assessing the effect of these manipulations on the disease phenotype. In my second Aim, I will define the contribution of tau to neurological dysfunction in Niemann-Pick C disease. I hypothesize that functional tau is required for increased autophagy in NPC1 deficient cells. I will use multiple assays to monitor the induction and flux of the autophagic pathway in NPCI/tau double-mutant primary neuronal cultures, and test the ability of wild type and mutant human tau to rescue autophagic defects in these cells. Further, I will determine the ability of human tau to rescue autophagic defects and the phenotype of Niemann-Pick C mice in vivo. The public health relevance of the proposed studies is that they will evaluate autophagy as a therapeutic target in Niemann-Pick C disease, and will elucidate the role of tau in neuropathology, thus improving our understanding of neurodegeneration in Niemann-Pick C and other tauopathies, including Alzheimer disease and the frontotemporal dementias. NOTE: The critiques of individual reviewers are provided in the following sections in an essentially unedited, verbatim form. They are provided to illustrate the range of opinions expressed. The application was discussed and assigned an overall score by all reviewers present. The critiques and the criterion scores were posted prior to the review meeting and may have not been updated or revised subsequent to the discussion at the meeting. Therefore, they may not represent the positions of the reviewers at the close of group discussion nor the final majority opinion of the group. The Resume and Summary of Discussion (above) represents the final outcome of the group discussion.