Florey Department of Neuroscience and Mental Health - Theses
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ItemInvestigating mechanisms of mutant huntingtin toxicity by spatially mapping lipid metabolites in a mouse model of Huntington’s disease( 2022)Huntington’s disease (HD) features intraneuronal inclusion body formation by polyglutamine-containing fragments of the mutant huntingtin protein in many brain regions, including the hippocampus, neocortex and striatum. To better understand the molecular changes associated with inclusion body formation and associated pathogenesis, we examined the abundances and turnover rates of membrane lipids in the hippocampus, a region of pronounced inclusion formation associated with cognitive deficits, in a transgenic mouse model of HD (R6/1 line) using deuterium labelling in vivo. The R6/1 HD mice lacked inclusions in the hippocampus at six weeks of age, whereas inclusions were extensive by 16 weeks. We assessed one brain hemisphere collected at three timepoints (6, 12 and 16 weeks) by MALDI-mass spectrometry imaging (MALDI-MSI) and the other hemisphere for liquid-chromatography mass spectrometry (LC-MS) analysis. Hippocampal sub-fields (CA1, CA3 and DG) dense with inclusions showed a reduction in the relative abundance of neuronal-enriched lipids with roles in neurotransmission, synaptic plasticity, neurogenesis and ER-stress protection. Conversely, lipids in the phosphatidylinositol, phosphatidic acid and ganglioside class were increased in lipid synthesis in HD mice, relative to WT mice across all the age groups examined. The changes were also detectable in the HD mice at six weeks of age, indicating they arose prior to the formation of the inclusion bodies and disease symptoms. Since elevated synthesis of lipids in the PI, PA and ganglioside classes is a known adaptive response to Endoplasmic reticulum (ER) stress, our findings suggest this molecular mechanism serves as an early-stage adaptive response to ER stress in pre-symptomatic HD mice and may be targetable therapeutically. Additionally, our study has identified progressive changes in neuronal lipid abundances in the pre-symptomatic and symptomatic stages of HD that closely correlate with known hippocampal-dependent cognitive changes in HD, thus providing early lipid biomarkers that may be targeted therapeutically to slow down HD progression. Most importantly, we have spatially monitored disturbances in lipid metabolism at the primary site of inclusions in HD hippocampi, thus illuminating new insight into the cascade of molecular events in brain regions spanning the development of inclusions in HD mice. These findings required the development of a novel in-house bioinformatics software (KineticMSI), which is made available as an R package and will have broad neuroimaging applications.