Longitudinal spatial mapping of lipid metabolites reveals pre-symptomatic changes in the hippocampi of Huntington's disease transgenic mice

• Published in: Neurobiology of disease Vol. 176; p. 105933
• Main Authors: Farzana, Farheen, McConville, Malcolm J., Renoir, Thibault, Li, Shanshan, Nie, Shuai, Tran, Harvey, Hannan, Anthony J., Hatters, Danny M., Boughton, Berin A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2023; Elsevier
• Subjects: Animals; Deuterium labelling; Disease Models, Animal; Hippocampus - metabolism; Huntingtin inclusions; Huntingtin Protein - genetics; Huntingtin Protein - metabolism; Huntington Disease - metabolism; In vivo metabolic activity; Kinetic mass spectrometry imaging (kMSI); Lipids; Mice; Mice, Transgenic; Neurodegeneration; Neuronal membrane lipids; Neurons - metabolism; Huntingtin inclusions; Deuterium labelling; In vivo metabolic activity; Neurodegeneration; Neuronal membrane lipids; Kinetic mass spectrometry imaging (kMSI)
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2022.105933

In Huntington's disease (HD), a key pathological feature includes the development of inclusion-bodies of fragments of the mutant huntingtin protein in the neurons of the striatum and hippocampus. To examine the molecular changes associated with inclusion-body formation, we applied MALDI-mass spectrometry imaging and deuterium pulse labelling to determine lipid levels and synthesis rates in the hippocampus of a transgenic mouse model of HD (R6/1 line). The R6/1 HD mice lacked inclusions in the hippocampus at 6 weeks of age (pre-symptomatic), whereas inclusions were pervasive by 16 weeks of age (symptomatic). Hippocampal subfields (CA1, CA3 and DG), which formed the highest density of inclusion formation in the mouse brain showed a reduction in the relative abundance of neuron-enriched lipids that have roles in neurotransmission, synaptic plasticity, neurogenesis, and ER-stress protection. Lipids involved in the adaptive response to ER stress (phosphatidylinositol, phosphatidic acid, and ganglioside classes) displayed increased rates of synthesis in HD mice relative to WT mice at all the ages examined, including prior to the formation of the inclusion bodies. Our findings, therefore, support a role for ER stress occurring pre-symptomatically and potentially contributing to pathological mechanisms underlying HD. •Neuron-enriched lipid abundances decline with age in inclusion dense hippocampal sub-fields of R6/1 HD mice.•Synthesis rates of certain lipid classes increases with age in HD mice.•Pre-symptomatic HD mice showed increased synthesis of lipids involved in adaptation to ER stress.•Disturbances in phosphatidylinositol (PI) metabolism in pre-symptomatic HD mice may signal impairment of synaptic plasticity.