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Investigation of LPIN1 and its Substrate, Phosphatidic Acid, as Modifiers of Niemann-Pick Type C disease

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thesis
posted on 2022-07-28, 01:15 authored by Liam Sargison

Niemann-Pick type C (NP-C) disease is a neurodegenerative disease with a typically paediatric onset, for which no satisfactory cure is available. Inheritance of two dysfunctional copies of either cholesterol transport gene NPC1 or NPC2 perpetrates substantial accumulation of sterols and secondary lipids within the lysosome, eventuating in devastating and progressive visceral and neurological symptoms. Although the disease is ostensibly monogenic, there is an impressive diversity among sufferers of the disease in regards to onset of disease, specific symptoms imposed and prognosis. Recently, genetic modifiers of the NP-C disease have been reported in several models, which have improved understanding of the disease and identified new targets for treatment. Accordingly, the relevance of the LPIN1 gene and the phosphatidic acid phosphatase activity of its enzyme, were investigated for their ability to modify the NP-C phenotype in a fibroblast and mouse model. Treatment of NP-C fibroblasts with inhibition of phosphatidic acid-generating enzymes DGK and PLD was ineffective in reducing the lysosomal accumulation of cholesterol. Likewise, Npc1-/-Lpin1-/- mice were largely indistinguishable from Npc1-/-, Lpin1-/- and wild-type mice at P0 for brain and liver lipid profiles, cerebellar histology and liver autophagy.

History

Copyright Date

2016-01-01

Date of Award

2016-01-01

Publisher

Te Herenga Waka—Victoria University of Wellington

Rights License

Author Retains Copyright

Degree Discipline

Biomedical Science

Degree Grantor

Te Herenga Waka—Victoria University of Wellington

Degree Level

Masters

Degree Name

Master of Biomedical Science

Victoria University of Wellington Unit

Centre for Biodiscovery

ANZSRC Socio-Economic Outcome code

920110 Inherited Diseases (incl. Gene Therapy)

ANZSRC Type Of Activity code

2 STRATEGIC BASIC RESEARCH

Victoria University of Wellington Item Type

Awarded Research Masters Thesis

Language

en_NZ

Victoria University of Wellington School

School of Biological Sciences

Advisors

Munkacsi, Andrew; Pfeffer, Peter