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Title: The role of the lysosome in innate immune function
Author: Newman, Stephanie
ISNI:       0000 0004 6497 6491
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2016
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Niemann-Pick disease type C (NPC) is a rare autosomal recessive neurodegenerative lysosomal storage disease caused by a mutation in the NPC1 or NPC2 genes. The functions of the proteins these genes encode are not fully understood, but are thought to be involved in cholesterol egress from the acidic compartment. The pathogenic cascade in proposed to begin with sphingosine accumulation followed by reduction of acidic store calcium levels. This results in impairing intracellular trafficking and storage of multiple lipid substrates in the late endosome/lysosomal compartment including cholesterol and multiple sphingolipids. Although clinically characterized by progressive neurodegeneration, there is also evidence of altered innate immune responses, such as neuroinflammation, that promotes disease progression. In this thesis, we initiated an investigation into whether phagocytosis, an important innate immune activity and the process by which particles are ingested by professional phagocytes, is defective in NPC. Our results indicate a global defect in phagocytosis that is not particle or size specific. We further found evidence of altered phagocytosis in vitro and in vivo that is likely contributing to NPC disease pathology and disease progression and may contribute to iron deficiency and Crohn's disease susceptibility in NPC patients. We next analysed lipid content on the plasma membrane. We found evidence to support the hypothesis that intracellular accumulation of lipids (e.g.glycosphingolipids) in NPC directly contributes to abnormal actin dynamics at the plasma membrane, leading to defective formation of phagocytic cups. When we reintroduced certain glycosphingolipids exogenously to the cells we were able to partially rescue the phagocytic defect suggesting that GM1 ganglioside may be a regulator of actin: plasma membrane contact sites. Lastly, we present evidence showing that some current NPC therapeutics partially correct the phagocytic defect. Taken together, this thesis provides insights into a novel aspect of NPC pathogenesis (innate immune dysfunction) and provides new knowledge of underlying immune defects in NPC, that in the future may act as novel targets for treatments.
Supervisor: Platt, Frances ; Platt, Nicholas Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available