The sphingolipid storage diseases are a group of ~40 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. Patients with this disease exhibit a clinically heterogeneous phenotype characterized by severe, progressive neurological impairment that is usually fatal in childhood. Data from several laboratories demonstrate that most cases of the disease are caused by loss-of-function mutations in the NPC1 gene, resulting in impaired intracellular trafficking of cholesterol and glycosphingolipids. Despite significant advances in understanding how NPC1 facilitates intracellular lipid transport, it remains poorly understood how mutations in this protein lead to the severe neuropathology by which this disorder is characterized. Recent studies from our laboratory and others have emphasized the need to define critical timing and cell types mediating pathogenesis so as to develop therapeutic strategies. This work also highlighted the importance of autophagy in neurodegenerative diseases including Niemann-Pick C. 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 hypotheses are that NPC1 deficiency leads to neurological impairment by exerting non-cell autonomous toxicity and by affecting CNS development, and that autophagy plays a protective role in Niemann-Pick C disease. These hypotheses are based on our preliminary analyses of mouse and cell based models where we established that NPC1 deficiency activates basal autophagy. An Npc1 conditional null mutant mouse that we recently developed will facilitate our work. Behavioral, histological, biochemical and genetic approaches will be used to establish the timing and cellular targets that are necessary for the development of neuropathology (Aim 1) and the role of autophagy in the Niemann-Pick C brain (Aim 2). The relevance of the proposed studies to public health is that they will further our understanding of mechanisms leading to neurological dysfunction, and may identify novel therapeutic targets for treating patients with Niemann-Pick C and related lipid storage diseases. 2.
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 may lead to the identification of novel therapeutic targets for treating patients with this disorder and related lipid storage diseases. PAGE ? PAGE ?3
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