Year

2021

Degree Name

Doctor of Philosophy

Department

School of Medicine

Abstract

Huntington’s disease (HD) is a genetic neurodegenerative disease that typically onsets in late adulthood as a series of progressive and terminal cognitive, psychiatric, and motor deficits. HD is caused by a CAG repeat expansion in the Huntingtin gene, which encodes an aberrant huntingtin protein, referred to as mutant huntingtin. Forty or more repeats assure clinical expression of HD, and longer repeats are associated with earlier onset and a more severe progression. Although mutant huntingtin is expressed ubiquitously, it causes region-specific degeneration of the striatum and areas of the cerebral cortex. Despite the identification of numerous pathological events in HD, none have yielded effective treatment options. Huntingtin naturally interacts with neural lipids in vitro; its interactions are changed when it is mutated in HD. Emerging evidence suggests that the lipid composition of brain regions can influence their susceptibility to pathological stimuli and evidence from HD human post-mortem, murine and cell models indicate region-specific disturbances to lipids in the brain. Lipids are involved in cell signalling, membrane formation, inflammation, neurotransmitter function, and the production of second messengers, and their involvement in numerous neurological conditions supports their contribution to neural function. This thesis aimed to investigate the region-specific disturbance to multiple lipid classes in advanced HD and relate these changes to a clinical measure (CAG repeat length). Post-mortem brain tissue from 13 advanced-stage HD and 13 age and sex matched controls was obtained from the Victorian Brain Bank. Targeted precursor ion mass spectrometry was used to measure extracted lipids from five brain regions of interest: caudate, putamen, cerebellum, and dorsomedial prefrontal cortex (grey and white matter). Western blots were used to measure the protein expression of key lipid enzymes. Analysis of approximately 190 lipid species revealed unique lipid signatures of disturbance in each brain region except for the grey matter of the dorsomedial prefrontal cortex.

In the caudate, ceramides, sphingomyelins and lactosylceramides were shifted according to fatty acyl chain length, favouring long over very long chain species in HD. In the putamen, total PC was decreased, and the relative abundance of PE species was altered, showing lower abundances of polyunsaturated fatty acids. Ester linked 22:6 derived from PC, PE and PS were also lower in HD putamen. Cholesteryl esters (CE) were increased in both striatal regions (caudate and putamen), with the caudate suggesting compensatory sequestration of cholesterol as esters. The white matter of the cortex had selective reductions in PC and PS in HD, with no change in the heavily myelin-associated PE. The cerebellum had increases in several lactosylceramide species with no other changes in lipid composition. CAG repeat length was not related to the abundance of any lipid, although it had negative correlations with ceramide synthase 1 (long chain sphingolipids) and acyl-CoA cholesterol acyltransferase 1 (CE). The interference of mutant huntingtin on lipids may be indirect through interactions with lipid enzymes and potentially cellular components. The disturbance to lipid metabolism in the HD brain is determinant on both the lipid and the brain region. Understanding the region-specific effects of the disease on neural lipid metabolism can contribute to the development and efficacy of lipid-based treatments for HD.

FoR codes (2008)

0301 ANALYTICAL CHEMISTRY, 1101 MEDICAL BIOCHEMISTRY AND METABOLOMICS, 1109 NEUROSCIENCES

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Unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the University of Wollongong.