Multiplatform metabolomic analysis of the R6/2 mouse model of Huntington’s disease

Hashimoto, Michie; Watanabe, Kenichi; Miyoshi, Kan; Koyanagi, Yukako; Tadano, Jun; Miyawaki, Izuru

doi:10.1002/2211-5463.13285

Cited by 13 publications

(5 citation statements)

References 54 publications

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“…Moving forward, the Land's cycle, and its potential temporal regulation of phospholipids, should be considered a metabolic pathway of interest in relation to HD progression. (For discussion of alternative hypotheses on the dysregulation of lipid and PC metabolism see [47]). Two metabolites dominated the separation of HD and control groups at 7 years, urea and threonine.…”

Section: Discussionmentioning

confidence: 99%

Metabolomic Analysis of Plasma in Huntington’s Disease Transgenic Sheep (Ovis aries) Reveals Progressive Circadian Rhythm Dysregulation

Spick

Hancox

Chowdhury

et al. 2023

JHD

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Background: Metabolic abnormalities have long been predicted in Huntington’s disease (HD) but remain poorly characterized. Chronobiological dysregulation has been described in HD and may include abnormalities in circadian-driven metabolism. Objective: Here we investigated metabolite profiles in the transgenic sheep model of HD (OVT73) at presymptomatic ages. Our goal was to understand changes to the metabolome as well as potential metabolite rhythm changes associated with HD. Methods: We used targeted liquid chromatography mass spectrometry (LC-MS) metabolomics to analyze metabolites in plasma samples taken from female HD transgenic and normal (control) sheep aged 5 and 7 years. Samples were taken hourly across a 27-h period. The resulting dataset was investigated by machine learning and chronobiological analysis. Results: The metabolic profiles of HD and control sheep were separable by machine learning at both ages. We found both absolute and rhythmic differences in metabolites in HD compared to control sheep at 5 years of age. An increase in both the number of disturbed metabolites and the magnitude of change of acrophase (the time at which the rhythms peak) was seen in samples from 7-year-old HD compared to control sheep. There were striking similarities between the dysregulated metabolites identified in HD sheep and human patients (notably of phosphatidylcholines, amino acids, urea, and threonine). Conclusion: This work provides the first integrated analysis of changes in metabolism and circadian rhythmicity of metabolites in a large animal model of presymptomatic HD.

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Section: Discussionmentioning

confidence: 99%

Metabolomic Analysis of Plasma in Huntington’s Disease Transgenic Sheep (Ovis aries) Reveals Progressive Circadian Rhythm Dysregulation

Spick

Hancox

Chowdhury

et al. 2023

JHD

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“…Minor changes to physiochemical properties as a function of lipid composition alters htt aggregation and lipid interactions in unique ways. This is a potential modifying factor to consider with respect to HD as changes to phospholipid metabolism (i.e., PC lipid metabolism) are observed in both HD patients (Mastrokolias et al, 2016 ; McGarry et al, 2020 ) and transgenic mouse models (Hashimoto et al, 2021 ; Tsang et al, 2006 ) as a function of disease progression. While differentiating individual lipids within a class, that is, saturated versus unsaturated PC lipids, is generally difficult there is interest in pursuing highly unsaturated fatty acids (HUFAs) as a treatment option for HD.…”

Section: Discussionmentioning

confidence: 99%

Cholesterol impacts the formation of huntingtin/lipid complexes and subsequent aggregation

et al. 2023

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Huntington's disease (HD) is a neurodegenerative disease resulting from an expansion of the polyglutamine (polyQ) domain within the huntingtin protein (htt). PolyQ expansion triggers toxic aggregation and alters htt/lipid interactions. The first 17 amino acids at the N‐terminus of htt (Nt17) have a propensity to form an amphipathic α‐helix crucial to aggregation and membrane binding. Htt interacts closely with a variety of membrane systems including those of the endoplasmic reticulum, mitochondria, nuclear envelope, and plasma membrane. Membrane composition heavily influences both htt aggregation and lipid interactions, and cholesterol is a crucial membrane component that modulates properties such as fluidity, permeability, and organization. In HD, cholesterol homeostasis is disrupted, and likely plays a role in toxicity. The objective of these studies was to identify the impact of cholesterol on htt aggregation and lipid interactions in various lipid systems. Lipid systems of POPC, DOPC, and POPG with varied levels of exogenously added cholesterol were exposed to htt, and the influences on aggregation, lipid binding, and htt/lipid complexation were evaluated using thioflavin‐T aggregation assays, atomic force microscopy, colorimetric lipid binding assays, and mass spectrometry. The addition of cholesterol to DOPC vesicles enhanced htt aggregation. In the presence of vesicles of either POPC or POPG, the addition of cholesterol reduced htt aggregation. Htt/lipid binding decreased for POPC and increased for both DOPC and POPG with increasing cholesterol content, with observed differences in htt/lipid complexation. Altered cholesterol content influences htt aggregation, lipid binding, and complexation differently depending on overall lipid composition.

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“…However, in a clinical follow-up of patients with HD, the administration of coQ10 even at very high doses did not demonstrate a meaningful attenuation of HD patients' functional decline [59,60]. Similarly, although preclinical studies of creatine conducted in R6/2 mice showed significant results [58,61], clinical experiments in patients with early stage HD failed [62]. These treatment failures require us to ask: can preclinical studies in current high-definition animal models correctly demonstrate the response in humans?…”

Section: Animal Studiesmentioning

confidence: 95%

Metabolomics: An Emerging “Omics” Platform for Systems Biology and Its Implications for Huntington Disease Research

Akyol,

Ashrafi,

Yilmaz

et al. 2023

Metabolites

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Huntington’s disease (HD) is a progressive, fatal neurodegenerative disease characterized by motor, cognitive, and psychiatric symptoms. The precise mechanisms of HD progression are poorly understood; however, it is known that there is an expansion of the trinucleotide cytosine-adenine-guanine (CAG) repeat in the Huntingtin gene. Important new strategies are of paramount importance to identify early biomarkers with predictive value for intervening in disease progression at a stage when cellular dysfunction has not progressed irreversibly. Metabolomics is the study of global metabolite profiles in a system (cell, tissue, or organism) under certain conditions and is becoming an essential tool for the systemic characterization of metabolites to provide a snapshot of the functional and pathophysiological states of an organism and support disease diagnosis and biomarker discovery. This review briefly highlights the historical progress of metabolomic methodologies, followed by a more detailed review of the use of metabolomics in HD research to enable a greater understanding of the pathogenesis, its early prediction, and finally the main technical platforms in the field of metabolomics.

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Multiplatform metabolomic analysis of the R6/2 mouse model of Huntington’s disease

Cited by 13 publications

References 54 publications

Metabolomic Analysis of Plasma in Huntington’s Disease Transgenic Sheep (Ovis aries) Reveals Progressive Circadian Rhythm Dysregulation

Metabolomic Analysis of Plasma in Huntington’s Disease Transgenic Sheep (Ovis aries) Reveals Progressive Circadian Rhythm Dysregulation

Cholesterol impacts the formation of huntingtin/lipid complexes and subsequent aggregation

Metabolomics: An Emerging “Omics” Platform for Systems Biology and Its Implications for Huntington Disease Research

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