Dysfunction of the Cholesterol Biosynthetic Pathway in Huntington's Disease
Open accessAbstract
The expansion of a polyglutamine tract in the ubiquitously expressed huntingtin protein causes Huntington's disease (HD), a dominantly inherited neurodegenerative disease. We show that the activity of the cholesterol biosynthetic pathway is altered in HD. In particular, the transcription of key genes of the cholesterol biosynthetic pathway is severely affected in vivo in brain tissue from HD mice and in human postmortem striatal and cortical tissue; this molecular dysfunction is biologically relevant because cholesterol biosynthesis is reduced in cultured human HD cells, and total cholesterol mass is significantly decreased in the CNS of HD mice and in brain-derived ST14A cells in which the expression of mutant huntingtin has been turned on. The transcription of the genes of the cholesterol biosynthetic pathway is regulated via the activity of sterol regulatory element-binding proteins (SREBPs), and we found an ∼50% reduction in the amount of the active nuclear form of SREBP in HD cells and mouse brain tissue. As a consequence, mutant huntingtin reduces the transactivation of an SRE-luciferase construct even under conditions of SREBP overexpression or in the presence of an exogenous N-terminal active form of SREBP. Finally, the addition of exogenous cholesterol to striatal neurons expressing mutant huntingtin prevents their death in a dose-dependent manner. We conclude that the cholesterol biosynthetic pathway is impaired in HD cells, mice, and human subjects, and that the search for HD therapies should also consider cholesterol levels as both a potential target and disease biomarker.
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Altered cholesterol, HDL and LDL metabolism, gene variants of APOA1, APOB, and APOE4, and decreased ApoA1 levels have been implicated in other neurologic disorders.
“Altered cholesterol, HDL and LDL metabolism, gene variants of APOA1, APOB, and APOE4, and decreased ApoA1 levels have been implicated in other neurologic disorders [21–35].”
From Sterol and lipid analyses identifies hypolipidemia and apolipoprotein disorders in autism associated with adaptive functioning deficits (2021) · cites this paper as [22]
The Introduction (page unavailable) links defects in cholesterol homeostasis to Niemann–Pick type C and Alzheimer’s disease, and the Discussion reports impaired cholesterol biosynthesis in Huntington’s disease. The paper does not establish the claimed links involving HDL or LDL metabolism, APOA1, APOB or APOE4 variants, or decreased ApoA1 levels. (LLM, conf=0.88)
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Cites
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“A pathological hallmark of Huntington's disease and other polyglutamine diseases is the presence of inclusions or aggregates of the expanded polyglutamine protein (Davies et al., 1997; Scherzinger et al., 1997).”
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- Authors
- Valenza, M., Rigamonti, D., Goffredo, D., Zuccato, C., Fenu, S., Jamot, L., Strand, A., Tarditi, A., Woodman, B., Racchi, M., Mariotti, C., Di Donato, S., Corsini, A., Bates, G., Pruss, R., Olson, J. M., Sipione, S., Tartari, M., & Cattaneo, E.
- Affiliations
- University of Milan (IT)
- Fred Hutch Cancer Center (US)
- Guy's Hospital (GB)
- University of Pavia (IT)
- University of Alberta (CA)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2005-10-26
- Volume
- 25
- Issue
- 43
- Pages
- 9932-9939
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6725556
- OpenAlex
- W2127294578
- Cited by
- 298
- References
- 2
- Citations by year
- 2026: 22 · 2025: 11 · 2024: 11 · 2023: 15 · 2022: 14 · 2021: 11 · 2020: 15 · 2019: 17 · 2018: 10 · 2017: 10 · 2016: 14 · 2015: 15 · 2014: 18 · 2013: 8 · 2012: 17
- FWCI
- 3.98
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- Hereditary Disease Foundation
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- Huntington's disease, cholesterol biosynthesis, huntingtin, polyglutamine expansion, SREBP, gene transcription, striatal neurons, cholesterol supplementation, neurodegeneration, disease biomarkers
- MeSH terms
- Analysis of Variance, Animals, Cells, Cultured, Cholesterol, Cytochrome P-450 Enzyme System, Dose-Response Relationship, Drug, Fibroblasts, Gene Expression Regulation, Humans, Huntington Disease, Hydroxymethylglutaryl CoA Reductases, Immunohistochemistry, Neurons, RNA, Messenger, Time Factors, Transfection, Blotting, Western, Cell Death, Reverse Transcriptase Polymerase Chain Reaction, Protein Transport, Oxidoreductases Acting on CH-CH Group Donors, Mice, Sterol Regulatory Element Binding Protein 1
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