Lipidomic Characterisation of the Human Huntington's Disease Brain

Huntington s disease HD is an inherited neurodegenerative disorder caused by a mutation in the huntingtin HTT gene Clinical symptoms encompass motor dysfunction cognitive decline and psychiatric disturbances and no approved therapy exists that delays disease progression Atrophy in the caudate nucleus CN and putamen are neuropathological hallmarks of HD A major site of neuroplasticity the subventricular zone SVZ is adjacent to the CN and shows promising albeit inefficient neurogenic responses in HD The molecular mechanisms underlying the pathogenesis of HD and the neurogenic response of the SVZ are incompletely understood Lipids are involved in both the regulation of adult neural stem cells in the SVZ and in neurodegeneration Moreover mutant HTT strongly associates with membranes which are predominantly comprised of glycerophospholipids sphingolipids and cholesterol Dysregulation in some lipids has been reported in HD however the involvement of lipids in HD is poorly understood and the lipidomic profile of the cytoarchitecturally unique SVZ has never been investigated Accordingly in this thesis I characterised the abundance and spatial distribution of hundreds of glycerophospholipids and sphingolipids in the CN and SVZ of human post mortem HD and neurologically normal brains Matrix assisted laser desorption ionisation imaging mass spectrometry was employed for unbiased lipidomic analysis of these regions with a bespoke statistical pipeline developed to identify lipids of pathological or anatomical interest which were assigned using Fourier transform ion cyclotron resonance and liquid chromatography tandem mass spectrometry The HD CN showed a lower abundance of docosahexaenoic and adrenic acid and also the key mitochondrial lipids cardiolipins The SVZ displayed a highly conserved lipidomic architecture that anatomically corresponded to its cytoarchitecture with defined lipid classes enriched in three of its four constituent laminae The molecular functions of these lipids were in keeping with the neurobiology of resident cell populations This lipidomic specialisation was profoundly disrupted in HD with a higher abundance of proinflammatory and proliferative sphingomyelin also observed This thesis provides evidence of significant lipidomic changes in HD that are biochemically consistent with mitochondrial dysfunction and oxidative stress in the CN and with inflammation in the SVZ These findings offer new avenues of investigation into the pathogenesis and ultimately the treatment of HD.