ArticleBrain : a journal of neurology2016
CYP46A1, the rate-limiting enzyme for cholesterol degradation, is neuroprotective in Huntington's disease.
Article in Brain : a journal of neurology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 110 papers, 1 of them a synthesis that pooled it.
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Who cites it
110 citing papers in PubMed, 1 synthesis or guideline pooled it, 181 citations in OpenAlex.
- Chronic cholesterol administration to the brain supports complete and long-lasting cognitive and motor amelioration in Huntington's disease.Pharmacological research · 2023Pooled it
- Efficacy and safety of efavirenz in Niemann-Pick disease type C.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Trial
- Sparse neuronal C4 elevation induces network-wide transcriptomic and lipid-droplet remodeling in the cortical microenvironment.PLoS computational biology · 2026Article
- Functional Validation of the Phase I-II-III Detoxification Pathway in Azumapecten farreri using Optimized RNA Interference Technology.Marine biotechnology (New York, N.Y.) · 2026Article
- Head-to-head comparison of [European journal of nuclear medicine and molecular imaging · 2026Article
- Cholesterol nose-to-brain delivery as a possible therapeutic strategy in Huntington's disease.Translational neurodegeneration · 2026Article
- ERH elicits cell lineage restriction in mammalian preimplantation development and differentiation from pluripotency via H3K9me3-heterochromatin.Nature communications · 2026Article
- Cholesterol at the Center of Alzheimer's Disease: A Unifying Hypothesis on the Pathogenic Mechanism.Molecules (Basel, Switzerland) · 2026Review
- CYP46A1 activation by low-dose efavirenz uncovers the link between brain cholesterol metabolism, energetics, and vasculature.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2026Article
- Cholesterol metabolism in neurodegenerative diseases: mechanisms and therapeutic advances.Molecular neurodegeneration · 2026Review
- Radiosynthesis and Evaluation ofACS medicinal chemistry letters · 2026Article
- Quantitative analysis of [European journal of nuclear medicine and molecular imaging · 2026Article
- Serotonergic Signaling Rewired: A Lipid Raft-Controlled Model of Synaptic Transmission Grounded in the Fundamental Parameters of Biological Systems.Life (Basel, Switzerland) · 2026Article
- The Neurolipid Atlas: a lipidomics resource for neurodegenerative diseases.Nature metabolism · 2025Article
- Cholesterol metabolic reprogramming mediates microglia-induced chronic neuroinflammation and hinders neurorestoration following stroke.Nature metabolism · 2025Article
- Sterol imbalances and cholesterol-24-hydroxylase dysregulation is linked to the underlying progression of multiple sclerosis.Brain pathology (Zurich, Switzerland) · 2025Article
- Astrocyte-neuron combined targeting for CYP46A1 gene therapy in Huntington's disease.Acta neuropathologica communications · 2025Article
- A review of the putative antiseizure and antiepileptogenic mechanisms of action for soticlestat.Epilepsia · 2025Review
- Brain Cytochrome P450: Navigating Neurological Health and Metabolic Regulation.Journal of xenobiotics · 2025Review
- The cholesterol 24-hydroxylase CYP46A1 promotes α-synuclein pathology in Parkinson's disease.PLoS biology · 2025Article
50 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Huntington's disease is an autosomal dominant neurodegenerative disease caused by abnormal polyglutamine expansion in huntingtin (Exp-HTT) leading to degeneration of striatal neurons. Altered brain cholesterol homeostasis has been implicated in Huntington's disease, with increased accumulation of cholesterol in striatal neurons yet reduced levels of cholesterol metabolic precursors. To elucidate these two seemingly opposing dysregulations, we investigated the expression of cholesterol 24-hydroxylase (CYP46A1), the neuronal-specific and rate-limiting enzyme for cholesterol conversion to 24S-hydroxycholesterol (24S-OHC). CYP46A1 protein levels were decreased in the putamen, but not cerebral cortex samples, of post-mortem Huntington's disease patients when compared to controls. Cyp46A1 mRNA and CYP46A1 protein levels were also decreased in the striatum of the R6/2 Huntington's disease mouse model and in SThdhQ111 cell lines. In vivo, in a wild-type context, knocking down CYP46A1 expression in the striatum, via an adeno-associated virus-mediated delivery of selective shCYP46A1, reproduced the Huntington's disease phenotype, with spontaneous striatal neuron degeneration and motor deficits, as assessed by rotarod. In vitro, CYP46A1 restoration protected SThdhQ111 and Exp-HTT-expressing striatal neurons in culture from cell death. In the R6/2 Huntington's disease mouse model, adeno-associated virus-mediated delivery of CYP46A1 into the striatum decreased neuronal atrophy, decreased the number, intensity level and size of Exp-HTT aggregates and improved motor deficits, as assessed by rotarod and clasping behavioural tests. Adeno-associated virus-CYP46A1 infection in R6/2 mice also restored levels of cholesterol and lanosterol and increased levels of desmosterol. In vitro, lanosterol and desmosterol were found to protect striatal neurons expressing Exp-HTT from death. We conclude that restoring CYP46A1 activity in the striatum promises a new therapeutic approach in Huntington's disease.
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