An imaging mass spectrometry atlas of lipids in the human neurologically normal and Huntington’s disease caudate nucleus

Abstract

Huntington's disease (HD) is a fatal disorder associated with germline trinucleotide repeat expansions in the HTT gene and characterised by striatal neurodegeneration. No efficacious interventions are available for HD, highlighting a major unmet medical need. The molecular mechanisms underlying HD are incompletely understood despite its monogenic aetiology. However, direct interactions between HTT and membrane lipids suggest that lipidomic perturbations may be implicated in the neuropathology of HD. In this study, we employed matrix‐assisted laser desorption/ionisation imaging mass spectrometry (MALDI–IMS) to generate a comprehensive, unbiased and spatially resolved lipidomic atlas of the caudate nucleus (CN) in human post‐mortem tissue from neurologically normal (n = 10) and HD (n = 13) subjects. Fourier transform‐ion cyclotron resonance mass spectrometry and liquid chromatography–tandem mass spectrometry were used for lipid assignment. Lipidomic specialisation was observed in the grey and white matter constituents of the CN and these features were highly conserved between subjects. While the majority of lipid species were highly conserved in HD, compared to age‐matched controls, CN specimens from HD cases in our cohort spanning a range of neuropathological grades showed a lower focal abundance of the neuroprotective docosahexaenoic and adrenic acids, several cardiolipins, the ganglioside GM1 and glycerophospholipids with long polyunsaturated fatty acyls. HD cases showed a higher focal abundance of several sphingomyelins and glycerophospholipids with shorter monosaturated fatty acyls. Moreover, we demonstrate that MALDI–IMS is tractable as a primary discovery modality comparing heterogeneous human brain tissue, provided that appropriate statistical approaches are adopted. Our findings support further investigation into the potential role of lipidomic aberrations in HD.

Proteomic Analysis of Huntington’s Disease Medium Spiny Neurons Identifies Alterations in Lipid Droplets

“…Further, cluster 3 links HD to altered inositol phosphate metabolism and phosphatidylinositol metabolic processes. Numerous studies link HD to alterations in lipid metabolism, and IPA analysis suggested APOE is a top upstream regulator ( 107 , 108 , 109 ). In addition, several of the lipid metabolism proteins significantly altered in HD-MSNs are regulators of lipid droplet formation ( 110 ).…”

Treatment with the Glycosphingolipid Modulator THI Rescues Myelin Integrity in the Striatum of R6/2 HD Mice

“…We have previously demonstrated that THI restored normal level of Glucosylceramide (GluCer) [ 18 ], a pivotal molecule in the synthesis of glycosphingolipids, whose levels have been reported to be increased in HD [ 18 , 40 , 41 ].…”

Lipidomic alterations in the cerebral cortex and white matter in sporadic Alzheimer’s disease

“…Our results are in line and go further from earlier studies showing differences in lipid composition between GM and WM (O’Brien and Sampson, 1965). Differences in the lipid composition between GM and WM have also been identified in the frontal lobe using MALDI-TOF mass spectrometry-imaging (Veloso et al, 2011) and flow infusion analysis coupled to Orbitrap™ mass spectrometry (Wood et al, 2021) in other brain regions as the temporal lobe (Man Lam et al, 2014) and the caudate nucleus (Hunter et al, 2021). Among the differential lipids in WM, we show the enrichment in lipid species belonging to the ether lipid class (alkyl and alkenyl ethers) mostly presented as TG, PC, and PE species.…”