Cholesterol 24-hydroxylase (CYP46A1) (CYP46A1)

Cholesterol 24-hydroxylase (CYP46A1) is a member of the cytochrome P450 superfamily and is the primary enzyme responsible for cholesterol elimination from the brain. Since cholesterol cannot cross the blood-brain barrier, CYP46A1 converts it into 24S-hydroxycholesterol (24S-OHC), a metabolite that can freely diffuse into the blood for hepatic clearance (UniProt Q9Y6A2). This pathway is essential for maintaining brain cholesterol homeostasis, which is frequently disrupted in neurodegenerative conditions such as Alzheimer's and Huntington's diseases (PubMed: 26437314). Therapeutic strategies targeting CYP46A1 include the use of adeno-associated virus (AAV) vectors, specifically AAVrh10, to deliver the CYP46A1 gene directly to the central nervous system to restore metabolic balance and reduce the accumulation of toxic proteins like amyloid-beta or mutant huntingtin (PubMed: 31511308). Additionally, small molecules like the HIV medication efavirenz have been found to act as allosteric activators of the enzyme at low doses, providing a pharmacological alternative to gene therapy. Clinical development of AAVrh10-CYP46A1 (e.g., LYS-SAF302) focuses on slowing disease progression by enhancing the clearance of cholesterol-rich lipid rafts that facilitate pathogenic protein aggregation.

Other names

Cytochrome P450 family 46 subfamily A member 1CP46Cholesterol 24-monooxygenaseCYP46

Enzymatic hydroxylation of cholesterol at the C-24 position to form 24S-hydroxycholesterol, which facilitates the efflux of cholesterol from the brain across the blood-brain barrier into systemic circulation.