The lysosomal storage diseases are a group of ~50 genetically distinct disorders that result from inherited deficiencies of lysosomal hydrolytic activities or lipid transport. Among this group is Niemann-Pick type C disease, an autosomal recessive disorder for which there is no effective treatment. Niemann-Pick C patients exhibit a clinically heterogeneous phenotype characterized by severe, progressive neurodegeneration that is usually fatal in childhood. Most cases are caused by loss-of-function mutations in the NPC1 gene, resulting in disrupted intracellular trafficking of cholesterol and glycosphingolipids. Although disease-causing mutations were identified almost two decades ago, it remains unknown how the resulting defects of lipid trafficking lead to the severe neurological disease that is characteristic of this disorder. This lack of knowledge hinders the identification of specific targets for developing disease-modifying therapies. The objective of this application is to identify mechanisms leading to neurodegeneration and to define cellular pathways where interventions could result in effective treatments. Our central hypothesis is that the disruption of cellular quality control pathways caused by Npc1 deficiency underlies neurodegeneration. This hypothesis springs from our analysis of patient fibroblasts and mice with a conditional null allele of the Npc1 gene generated in our lab. These studies and results in the literature revealed impairments of cellular proteostasis, including abnormalities in autophagy, that result in the accumulation of ubiquitinated proteins and fragmented mitochondria, particularly within neurons and in CNS regions of selective vulnerability. Our studies also build on our preliminary data demonstrating unexpected contributions of oligodendrocytes to neuronal degeneration in the mutant brain, suggesting impaired support of neurons by glia. These findings are complemented by recent work characterizing a new mouse model of disease that expresses Npc1 I1061T, the most prevalent disease-causing mutation. Behavioral, histological, biochemical, cell biological and genetic approaches will be used to characterize alterations in autophagy in Npc1 deficient neurons (Aim 1), establish the contribution of altered energy metabolism to axonal pathology and neuron loss (Aim 2), and identify critical components of the machinery that regulates degradation of Npc1 I1061T (Aim 3). These studies are expected to have an important positive impact by defining mechanisms through which Npc1 deficiency leads to progressive neurodegeneration and by identifying potential therapeutic targets. Furthermore, we expect that shared mechanisms mediate toxicity in several lipid storage diseases, suggesting that advances here will impact our understanding and treatment approaches to genetically distinct lysosomal storage disorders.
The relevance of the proposed studies to public health is that they will help unravel the mechanisms of neurodegeneration in Niemann-Pick C disease. Understanding these pathways is the first step toward the identification of disease-modifying therapies for patients with this disorder and related lipid storage diseases.
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