ArticlePLoS biology2025
The cholesterol 24-hydroxylase CYP46A1 promotes α-synuclein pathology in Parkinson's disease.
Article in PLoS biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers, 1 of them a synthesis that pooled it.
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Who cites it
13 citing papers in PubMed, 1 synthesis or guideline pooled it.
- When bad turns good: a systematic review on cholesterol and LDL in longitudinal patient cohorts with Parkinson's disease.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2026Pooled it
- Head-to-head comparison of [European journal of nuclear medicine and molecular imaging · 2026Article
- Lipid Metabolism Reprogramming in the Aging Brain: Glial-Mediated Pathogenic Mechanisms and Translational Strategies in Neurodegeneration.International journal of molecular sciences · 2026Review
- Cholesterol metabolism in neurodegenerative diseases: mechanisms and therapeutic advances.Molecular neurodegeneration · 2026Review
- Neuronal Cholesterol Deficiency Mediated by Astrocytic SREBP2 Downregulation Leads to Postoperative Cognitive Dysfunction Through Impairment of Hippocampal Synaptic Plasticity and Excitatory Synaptic Transmission.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Physiological Functions of Side-Chain-Retaining Sterols in the Brain and Their Roles in Neurodegenerative Diseases.Metabolites · 2026Review
- Serum total cholesterol and low-density lipoprotein cholesterol are associated with Parkinson's disease in East Asian populations: a bidirectional Mendelian randomization study with complementary animal observation.Frontiers in aging neuroscience · 2026Article
- Autoimmune signatures in neurodegenerative dementias: from peripheral immune activation to CNS pathology.Frontiers in immunology · 2026Review
- Single-cell, multi-region profiling of the macaque brain across the lifespan.bioRxiv : the preprint server for biology · 2025Article
- Frequency-Dependent Mechanism of 24-Hydroxycholesterol-Mediated Modulation of Neurotransmitter Release at the Mouse Neuromuscular Junction: The Role of Reactive Oxygen Species.Neurochemical research · 2025Article
- Differential roles of individual bile acid in physiology and disease.Pharmacological research · 2025Review
- CYP51A1 in health and disease: from sterol metabolism to regulated cell death.Cell death discovery · 2025Review
- Protein regulatory network mediated by palmitoylation modifications in the pathological progression of Parkinson's disease: a narrative review.Frontiers in immunology · 2025Review
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12 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Parkinson's disease (PD) is a neurodegenerative disease characterized by the death of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies that are composed of aggregated α-synuclein (α-Syn). However, the factors that regulate α-Syn pathology and nigrostriatal dopaminergic degeneration remain poorly understood. Previous studies demonstrate cholesterol 24-hydroxylase (CYP46A1) increases the risk for PD. Moreover, 24-hydroxycholesterol (24-OHC), a brain-specific oxysterol that is catalyzed by CYP46A1, is elevated in the cerebrospinal fluid of PD patients. Herein, we show that the levels of CYP46A1 and 24-OHC are elevated in PD patients and increase with age in a mouse model. Overexpression of CYP46A1 intensifies α-Syn pathology, whereas genetic removal of CYP46A1 attenuates α-Syn neurotoxicity and nigrostriatal dopaminergic degeneration in the brain. Moreover, supplementation with exogenous 24-OHC exacerbates the mitochondrial dysfunction induced by α-Syn fibrils. Intracerebral injection of 24-OHC enhances the spread of α-Syn pathology and dopaminergic neurodegeneration via elevated X-box binding protein 1 (XBP1) and lymphocyte-activation gene 3 (LAG3) levels. Thus, elevated CYP46A1 and 24-OHC promote neurotoxicity and the spread of α-Syn via the XBP1-LAG3 axis. Strategies aimed at inhibiting the CYP46A1-24-OHC axis and LAG3 could hold promise as disease-modifying therapies for PD.
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