Niemann-Pick Type C Disease: Protective Mechanisms from Neurodegeneration and Targets for Therapeutic Intervention.

[摘要] Niemann-Pick type C (NPC) disease is a lysosomal storage disorder that causes progressive neurodegeneration and early death, often in children. The two disease-causing proteins, NPC1 and NPC2, are involved in the movement of unesterified cholesterol out of late endosomes and lysosomes (LE/Lys). Loss-of-function mutations in the NPC1 or NPC2 genes lead to the accumulation of unesterified cholesterol and glycosphingolipids in LE/Lys. NPC disease is characterized by severe neurological symptoms including ataxia, cognitive decline, seizures, dystonia, and vertical gaze palsy. The mechanism underlying this neurodegeneration has not been identified, and there is no effective treatment for the disease. This dissertation aims to characterize a pathway leading to neuronal death and several modifier genes that promote neuronal survival in NPC disease. This work may provide a foundation for future studies that could lead to the development of novel therapies. Chapter 1 introduces the genetics and pathology of NPC disease, and reviews lysosomal proteases and heat shock protein beta-1 (HSPB1). After reviewing the known factors involved in NPC disease, chapter 2 presents studies demonstrating that cystatin B (CSTB), an endogenous inhibitor of cathepsins B, H, and L, protects Purkinje cells against cerebellar degeneration in a mouse model of NPC disease. Chapter 3 presents research that seeks to identify genes that may be neuroprotective or create vulnerability in the NPC brain, using the Allen Brain Atlas. One candidate gene, HSPB1, is confirmed to promote neuronal survival in cellular and mice models of NPC disease, and the mechanism by which HSPB1 protects cells from NPC deficiency is shown. Finally, chapter 4 summarizes these findings, discusses relevant questions that remain open, and suggests future directions for work in this area. The work described in this thesis will help us understand the pathways leading to neurodegeneration in NPC disease. It is my hope that this knowledge will enable the identification of targets for the future development of disease modifying therapies.

[发布机构] University of Michigan

[效力级别] Cystatin B (CSTB)

[关键词] Niemann-Pick type C (NPC);Cystatin B (CSTB);Heat shock protein beta-1 (HSPB1);Neurodegeneration in NPC disease;Cathepsins mislocalization;Molecular;Cellular and Developmental Biology;Science (General);Science;Molecular and Cellular Pathology