# MOLECULAR PATHOGENESIS STUDIES OF RETT SYNDROME

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $389,213

## Abstract

Project Summary
Rett syndrome (RTT) is a severe neurodevelopmental disorder with postnatal onset. Caused by loss-of-function
mutations in the X-linked gene methyl CpG binding protein 2 (MECP2), girls with classic RTT develop
normally for the first ~12-18 months of life, reaching the expected milestones, but then lose their acquired
skills over a period of weeks and instead develop stereotypies, ataxia, apraxia, seizures, and a host of other
symptoms. Milder mutations that primarily reduce the amount of MeCP2 protein produced cause milder
symptoms that take longer to manifest. Various mouse models of RTT (male Mecp2 nulls, female
heterozygotes, mice bearing specific disease-causing mutations) faithfully reproduce this natural history
(normal health, regression, and deterioration). Strikingly, deletion of the gene in adulthood reproduces the full
phenotype, whereas expression of Mecp2 in adult null mice rescues it, demonstrating that MeCP2 has some as-
yet-unspecified function that is critical for neuronal maintenance. Although gene therapy would seem the best
hope, the mosaic nature of MeCP2 in females (~50% of neurons will have wild-type MeCP2) presents a difficult
challenge for this approach, as too much MeCP2 also causes disease (MECP2 duplication syndrome [MDS],
which is every bit as devastating). Therefore, in our search for viable therapeutic options, we are guided by two
principles: the period of early normal development provides a window of opportunity to intervene and delay
onset, and the lag between loss of MeCp2 and appearance of symptoms (or reversal of symptoms, in the context
of rescuing MDS) means there is a cascade of molecular events that, if we could but map them, should allow us
to identify key genes or pathways that could serve as therapeutic targets and biomarkers of treatment response.
Having previously found that forniceal deep brain stimulation improves learning and memory in RTT mice, we
hypothesized that motor training during the presymptomatic period might also stimulate the neural circuits
and delay symptom onset. Indeed, this proved to be the case. We now seek to trace the cascade of molecular
and cellular changes that occur after MeCP2 depletion but before the onset of symptoms to define initiators of
RTT pathogenesis and biomarkers of response as we stimulate the brain through intensive training or raise
MeCP2 levels in the context of hypomorphic mutations. In our first aim, we will identify the transcriptional
changes that take place in task-specific neurons that respond to intensive training with improved function,
electrophysiology, and morphology. In aim 2, we will trace the cascade of molecular, epigenetic, and cellular
changes that follow for several weeks after acute MeCP2 depletion, and that eventually lead to neurological
dysfunction. In aim 3, we will upregulate MeCP2 levels in two distinct RTT mouse models, each carrying
mutations that reduce MeCP2 levels, to determine the extent of improvement.

## Key facts

- **NIH application ID:** 10834017
- **Project number:** 5R01NS057819-19
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** HUDA Y ZOGHBI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $389,213
- **Award type:** 5
- **Project period:** 2006-09-04 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10834017

## Citation

> US National Institutes of Health, RePORTER application 10834017, MOLECULAR PATHOGENESIS STUDIES OF RETT SYNDROME (5R01NS057819-19). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10834017. Licensed CC0.

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