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Title: Investigating ion dyshomeostasis in Niemann-Pick disease type C, both in vitro and in vivo
Author: Maguire, Emily
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2017
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This thesis investigated ion dyshomeostasis within Niemann-Pick disease type C (NPC), a neurodegenerative lysosomal storage disease. Chapter 3 characterizes newly discovered lysosomal Zn2+ storage in NPC, and identifies a novel function for the NPC1 protein as a lysosomal Zn2+ transporter. Zn2+ accumulation appears responsible for some lipid storage within NPC, and treating cells with the Zn2+ chelator phytic acid corrects downstream NPC phenotypes. Chapter 4 investigates Ca2+-modulating therapies for treating NPC. These include tanganil, demonstrated in a recent case study to ameliorate ataxia within NPC patients, and which works by increasing cytosolic Ca2+ to overcome the NPC lysosomal Ca2+ signaling defect. The importance of this Ca2+ signaling defect in NPC can be seen both in the aforementioned beneficial effects of Ca2+ modulating therapies and when looking at NPC-like lipid storage and reduced neuronal Ca2+ spikes observed following treatment of zebrafish with an inhibitor of lysosomal Ca2+ signaling, Ned-19 (Chapter 5). In addition, Chapter 5 describes the generation and characterization of NPC zebrafish treated with inhibitors of npc1 (U18666A, 1NMP) and microinjected with npc1-morpholino. These models accurately recapitulate human NPC phenotypes (characteristic lipid storage, behavioural defects) and can be used to test emerging NPC therapies in vivo (e.g. phytic acid, tanganil). Finally, Chapter 6 explores how different formulations of curcumin, which correct NPC phenotypes both in vitro and in vivo via Ca2+ modulation, have reduced effect and can exacerbate storage in cells when combined with lipid vectors. Having described studies into both Ca2+ and Zn2+ dyshomeostasis in NPC, a new 2-armed pathogenic cascade was hypothesized whereby early dyshomeostasis of lysosomal Ca2+ and Zn2+ generates all downstream NPC phenotypes. Combination therapies with Ca2+ modulators (e.g. tanganil) and Zn2+ chelators (e.g. phytic acid) may provide the best option to treat this complex disease, and require testing both in vitro and in vivo.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available