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Neuronal Cholesterol Homeostasis Enzyme CYP46A1 in the Pathophysiology of Rett Syndrome

Award Number: R21NS147521
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Neuronal Cholesterol Homeostasis Enzyme CYP46A1 in the Pathophysiology of Rett Syndrome - PROJECT SUMMARY / ABSTRACT Rett syndrome (RTT), caused by mutations in MECP2, is a complex neurological disorder characterized by myriad physiological disruptions. The overwhelming complexity of this disorder likely lies in the fact that MECP2 regulates numerous genes and cellular pathways across different cell types and specific developmental stages, proving a challenge to therapeutic treatments. Although approaches such as exogenous re-expression of MECP2 or reactivation of the silenced allele offer great hope for a cure for RTT, there are many challenges to their application in humans. It may be more feasible in the short term to use therapeutic interventions that can target cellular pathways associated with Mecp2 loss-of-function and that are approved for therapeutic use. Our prior work demonstrated that vitamin D, a simple, cost-effective dietary supplement can improve several RTT phenotypes due to its ability to modulate multiple cellular pathways disrupted in RTT, including NF-kB, BDNF, IGF1, and the PI3K/AKT pathway We have additionally found that reduced expression of Cyp46a1 in female heterozygous Mecp2+/- neocortex is rescued with vitamin D supplementation, suggesting it could contribute to the pathophysiology of RTT and the rescue of phenotypes. Reduced expression of Cyp46a1, a neuronal-specific gene and a key enzyme involved in cholesterol homeostasis in the brain, is observed in multiple neurological disorders, suggesting that tightly controlled regulation of its expression is essential for neurological function. The overall goal of the proposed work is thus to determine whether modulation of Cyp46a1 could provide a viable partial therapeutic target for RTT. CYP46A1 is expressed exclusively by neurons and catabolizes cholesterol to 24S-hydroxycholesterol (24S-OHC), allowing it to diffuse across the blood-brain barrier for turnover. Importantly, 24-OHC itself regulates synaptic function by modulating NMDA receptor-mediated EPSCs. Cholesterol cannot cross the blood-brain-barrier and must be synthesized in situ, by astrocytes. Cholesterol homeostasis in the brain thus involves a complex interplay between neurons and astrocytes; either insufficient or excess neuronal cholesterol impairs memory formation and synaptic plasticity. We propose to investigate whether reduction of CYP46A1 correlates with RTT phenotype regression, and whether activating this critical enzyme rescues Mecp2- null cortical neuronal phenotypes (Aim 1). We propose to further determine whether Mecp2-null astrocytes contribute to the disrupted cholesterol homeostasis (Aim 2). These studies will address a major gap in knowledge on the mechanisms of cholesterol homeostasis disruptions in RTT brain, and they are essential to determine the therapeutic potential of Cyp46a1 modulation. Reduced expression of CYP46A1 is currently being studied as a therapeutic target in Huntington’s and Alzheimer’s, raising the important potential to apply established therapeutics to RTT.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $224,250 )
2026	2026	SYRACUSE UNIVERSITY	900 S CROUSE AVE	SYRACUSE	NY	13244	ONONDAGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/13/2026	NEW	$224,250
														Subtotal = $224,250

Grand Total All Awards = $224,250

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Neuronal Cholesterol Homeostasis Enzyme CYP46A1 in the Pathophysiology of Rett Syndrome

Award Number: R21NS147521

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/15/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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