# Dysregulated Cholesterol Clearance via CYP46A1 Contributes to Cerebellar Sterol Imbalance in Mecp2-Null Mice

## TL;DR

This study shows that disrupted cholesterol clearance in the cerebellum of Rett syndrome mice leads to a buildup of cholesterol, potentially contributing to the disease's neurological symptoms.

## Contribution

The study identifies impaired CYP46A1 expression as a novel mechanism for cerebellar cholesterol imbalance in Rett syndrome.

## Key findings

- Total cholesterol levels are significantly elevated in cerebellar tissue and synaptosomes of Mecp2-null mice.
- CYP46A1 expression is markedly reduced, indicating defective cholesterol clearance rather than increased synthesis.
- Cholesterol biosynthetic regulators show no significant changes in expression.

## Abstract

Rett syndrome (RTT) is a neurodevelopmental disorder characterized by motor deficits, partly attributed to cerebellar dysfunction. RTT is primarily caused by mutations in the gene encoding the methyl-CpG-binding protein 2 (MECP2), which has been implicated in cholesterol homeostasis by mechanisms that remain poorly understood. Given that brain cholesterol is primarily synthesized de novo and that disrupted cholesterol homeostasis is linked to various neurological disorders, we aimed to investigate cholesterol regulation in the cerebellum of Mecp2-null mice, a well-established RTT model. We measured total cholesterol levels in cerebellar tissue and cerebellar synaptosomes and assessed the expression of genes involved in cholesterol biosynthesis and intracellular transport. Our results show significantly elevated total cholesterol in both cerebellar tissue and synaptosomes. Furthermore, we identified a marked reduction in CYP46A1 expression, which is essential for the elimination of encephalon sterols. In contrast, key cholesterol biosynthetic regulators (Srebp2, Hmgcs1, Sqle) showed no significant changes in expression, suggesting an impaired cerebellar cholesterol turnover—driven by defective clearance—rather than enhanced synthesis may underlie the metabolic imbalance observed in the cerebellum of the RTT mouse model. Altogether, these findings provide a mechanistic insight into how MeCP2 deficiency disrupts cerebellar cholesterol homeostasis and highlight cholesterol clearance pathways as potential contributors to RTT pathology and a factor to consider for further RTT therapeutic approaches.