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CC BY-NC-ND V4.0, Open Access
Journal article
Longitudinal spatial mapping of lipid metabolites reveals pre-symptomatic changes in the hippocampi of Huntington?s disease transgenic mice
Neurobiology of disease, Vol.176, 105933
2023
PMID: 36436748
Abstract
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 (presymptomatic), 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.
Details
- Title
- Longitudinal spatial mapping of lipid metabolites reveals pre-symptomatic changes in the hippocampi of Huntington?s disease transgenic mice
- Authors/Creators
- Farheen Farzana - The University of MelbourneMalcolm J. McConville - The University of MelbourneThibault Renoir - Florey Institute of Neuroscience and Mental HealthShanshan Li - Florey Institute of Neuroscience and Mental HealthShuai Nie - The University of MelbourneHarvey Tran - Florey Institute of Neuroscience and Mental HealthAnthony J. Hannan - Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Melbourne, Vic 3010, AustraliaDanny M. Hatters - The University of MelbourneBerin A. Boughton - Murdoch University, Centre for Computational and Systems Medicine
- Publication Details
- Neurobiology of disease, Vol.176, 105933
- Publisher
- Elsevier
- Number of pages
- 18
- Grant note
- APP1184166 / National Health and Medical Research Council (NHMRC); National Health and Medical Research Council (NHMRC) of Australia
- Identifiers
- 991005588669407891
- Copyright
- © 2022 Published by Elsevier Inc.
- Murdoch Affiliation
- Australian National Phenome Centre
- Language
- English
- Resource Type
- Journal article
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- Collaboration types
- Domestic collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.52 Neurodegenerative Diseases
- 1.52.951 Huntington's and Ataxias
- Web Of Science research areas
- Neurosciences
- ESI research areas
- Neuroscience & Behavior