Evidence for altered cholesterol metabolism in H untington's disease post mortem brain tissue
Abstract
AIMS: Cholesterol plays an essential role in membrane structure and function, being especially important in the brain. Alteration of brain cholesterol synthesis and metabolism has been demonstrated in several Huntington's disease (HD) mouse and cell models; however, less is known about these alterations in human tissue. This study aimed to identify alterations to cholesterol synthetic and metabolic pathways in human HD brain tissue. METHODS: A broad range of cholesterol synthetic precursors, metabolites and oxidation products were measured by gas chromatography-tandem mass spectrometry in five regions of human post mortem HD brain and compared with age- and sex-matched control tissues. The level of enzymes that regulate cholesterol homeostasis, cholesterol 24-hydroxylase and delta(24)-sterol reductase were investigated by Western blotting and qPCR in putamen. RESULTS: The most significant changes were localized to the putamen, where a 60% decrease in 24(S)-hydroxycholesterol, 30% increase in cholesterol and 100-200% increase in synthetic precursors (lathosterol, zymosterol and desmosterol) was detected. The enzymes cholesterol 24-hydroxylase and delta(24)-sterol reductase were also significantly decreased in HD putamen as compared with control tissues. Free radical-generated cholesterol oxidation products 7-keto cholesterol and 7β-hydroxycholesterol were also increased by 50-70% in HD putamen. CONCLUSION: Human HD brain has significantly decreased cholesterol metabolism and disrupted cholesterol homeostasis. Our data also indicate that lipid oxidative stress accompanies HD pathology.
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Dysregulation of cholesterol metabolism and oxysterol accumulation are associated with AMD as well as other pathologies involving oxidative stress such as Huntington's disease, atherosclerosis, and cystic fibrosis.
“Dysregulation of cholesterol metabolism and oxysterol accumulation are also associated with AMD as well as other pathologies involving oxidative stress such as Huntington’s disease, atherosclerosis, and cystic fibrosis (Iuliano et al., 2003, 2009; Jenner et al., 2007; Kreilaus et al., 2016).”
From Microtubule-associated protein 1 light chain 3B, (LC3B) is necessary to maintain lipid-mediated homeostasis in the retinal pigment epithelium (2018) · cites this paper as Kreilaus et al., 2016
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- Authors
- Kreilaus, F., Spiro, A. S., McLean, C. A., Garner, B., & Jenner, A. M.
- Affiliations
- University of Wollongong (AU)
- The Alfred Hospital (AU)
- Corresponding author
- Kreilaus, Fabian
- Jenner, Andrew M.
- Venue
- Neuropathology and Applied Neurobiology
- Publisher
- Wiley
- Published
- 2015-10-15
- Volume
- 42
- Issue
- 6
- Pages
- 535-546
- ISSN
- 0305-1846 (ISSN-L)
- 1365-2990
- OpenAlex
- W2128775004
- Cited by
- 92
- References
- 69
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 13 · 2023: 14 · 2022: 7 · 2021: 11 · 2020: 4 · 2019: 12 · 2018: 5 · 2017: 3 · 2016: 4
- FWCI
- 4.03
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuropathology and Applied Neurobiology (publishedVersion)
- PubMed (publishedVersion)
- Research Online (University of Wollongong) (submittedVersion)
- Figshare (submittedVersion)
- Funders
- University of Wollongong (#1030328)
- Parkinson’s Victoria
- Ministry of National Defense
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- Huntington's disease, cholesterol metabolism, cholesterol homeostasis, putamen, 24S-hydroxycholesterol, cholesterol 24-hydroxylase, cholesterol oxidation products, 7-ketocholesterol, 7β-hydroxycholesterol, lipid oxidative stress, postmortem brain, lathosterol, zymosterol, desmosterol
- MeSH terms
- Aged, Aged, 80 and over, Autopsy, Brain, Cholesterol, Female, Humans, Huntington Disease, Male, Middle Aged
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