# Investigating mitochondrial dysfunction in human astrocytes with RTT-causing MECP2 mutations

> **NIH NIH R01** · STATE UNIVERSITY NEW YORK STONY BROOK · 2024 · $398,750

## Abstract

Summary
Mutations in the X-linked gene, methyl-CpG binding protein 2 (MECP2), underlie a wide range of
neuropsychiatric disorders, most commonly Rett syndrome (RTT), a severe neurodevelopmental disorder.
Despite numerous studies, why the loss of MeCP2 function results in RTT remains largely obscure, and it
represents a major challenge from both basic biological and therapeutic standpoints. Our previous studies,
based on mouse models, advanced the knowledge of the disease and the specific cell types involved in RTT
neuropathology. We showed that mutant glia, specifically astrocytes, are an integral part of RTT and that
healthy astrocytes can rescue many aspects of the disease. However, mouse models do not faithfully
represent human RTT, which is known to be more severe than in mouse models. Importantly, human
astrocytes are significantly different from mouse astrocytes in their structure, gene expression landscape,
mitochondrial physiology, energy metabolism, and susceptibility to oxidative stress and hypoxia. For this
reason, we have recently established human stem cell-based models for RTT to investigate the cellular and
molecular features of human astrocytes bearing RTT-causing mutations in MECP2. Our studies revealed
significant aberrations in mutant human astrocytes, including aberrant gene expression landscape, impaired
structural complexity, and impaired metabolic homeostasis. Importantly, we showed significant aberrations in
mitochondrial morphology and function in mutant astrocytes, suggesting that dysfunctional mitochondria likely
lie at the heart of the impaired metabolic homeostasis in mutant astrocytes. Furthermore, our preliminary data
show the presence of senescence markers in mutant astrocytes, suggesting that mitochondrial dysfunction
likely leads to cellular senescence in mutant astrocytes. Thus, we propose to build on our recent findings and
identify the common aberrations in gene expression in human astrocytes bearing different MECP2 mutations
with a focus on genes involved in mitochondrial function (Aim 1), investigate whether mitochondrial dysfunction
is a common and specific feature of mutant human astrocytes bearing different MECP2 mutations and whether
mitochondrial dysfunction leads to a specific type of cellular senescence in all mutant astrocytes (Aim 2).
Importantly, we will examine whether rescuing mitochondrial dysfunction and/or cellular senescence could
ameliorate the structural and functional abnormalities we identified in mutant astrocytes and thereby their
ability to properly support neurons (Aim 3).
 Understanding the molecular mechanisms that underlie mitochondrial dysfunction and its downstream
effects on MECP2 mutant human astrocytes, and whether rescuing mitochondrial dysfunction and/or
senescence could ameliorate the structural and functional aberrations of mutant astrocytes and consequently
restore their support to neurons, is highly important for developing therapeutic strategies for RTT.

## Key facts

- **NIH application ID:** 10859782
- **Project number:** 1R01NS136519-01
- **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK
- **Principal Investigator:** Nurit Ballas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $398,750
- **Award type:** 1
- **Project period:** 2024-05-05 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10859782

## Citation

> US National Institutes of Health, RePORTER application 10859782, Investigating mitochondrial dysfunction in human astrocytes with RTT-causing MECP2 mutations (1R01NS136519-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10859782. Licensed CC0.

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