# Mitochondrial ROS and Microglia in Rett Syndrome

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $321,418

## Abstract

Project Summary/Abstract
 Rett syndrome (RTT), a devastating neurodevelopmental disorder, is largely caused by loss-of-function
mutations in the X-linked gene encoding the epigenetic regulator MeCP2. Our group was the first to show a
detrimental role of microglial abnormalities in a MECP2 knockout (MECP2-KO) mouse model of RTT. Recent
in vivo data suggest that correcting microglial abnormalities is sufficient to rectify major RTT-like symptoms in
this model. Therefore, how MeCP2 deficiency causes microglial abnormalities and how the functional states of
MeCP2-deficient microglia (RTT-MG) influence RTT pathology is a critical question. Recently we found that
MeCP2 deficiency in RTT-MG resulted in enhanced mitochondrial reactive oxygen species (mtROS)
production, which we hypothesize would lead to metabolic derangements and abnormal microglial functions.
Interestingly, in vitro studies showed that several key RTT-MG abnormalities were rescued by mitochondria-
targeted transgene mCAT (the antioxidant enzyme catalase being expressed only in mitochondria, which
usually do not harbor catalase) and two FDA-approved mitoactive Nrf2 activators, opening a possibility for
intervention. Our preliminary data further showed that global expression of mCAT (GL-mCAT) prolonged the
lifespan and improved motor and respiratory functions of the MECP2-KO mice, supporting the promise of our
approach in a whole animal setting. Here we propose to extend this line of research to gain a deeper
understanding of how MeCP2 is related to functional and pathological states of microglia, and to generate
preclinical proof of principle that is instrumental for developing novel therapies for RTT:
Aim 1: Determine the pathological role of microglial mtROS in vivo: Several lines of evidence support that
microglia abnormalities drive the progression of RTT. We have shown that global expression of mCAT
ameliorates the RTT-like phenotype in MECP2-KO mice. Based on this encouraging result, we further
hypothesize that quenching mtROS selectively in microglia to rectify microglial abnormalities will also
ameliorate RTT-like deficits in MECP2-KO mice. For this aim, we will generate and analyze the phenotype and
microglial pathology of MECP2-KO/MG-mCAT mice with microglia-targeted expression of mCAT. The result
would support the role of microglial mtROS in the pathogenesis of RTT.
Aim 2: Determine the role of mtROS in pathological characteristics and functional responsiveness of RTT
microglia: Our previous data, mostly in vitro work, support the hypothesis that mtROS-related
metabolic/molecular derangements lead to RTT-MG abnormalities including the loss of the “metabolic
flexibility” required to drive their functional responsiveness. Now in this aim we will test this hypothesis in vivo,
mainly by analyzing microglia acutely isolated from MECP2-KO and MECP2-KO/mCAT mice. We will
determine if mCAT, expressed in vivo, is able to (a) rectify the metabolic/molecular derangements of RTT-MG,
and (...

## Key facts

- **NIH application ID:** 9975010
- **Project number:** 5R01HD088832-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** LEE-WAY JIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $321,418
- **Award type:** 5
- **Project period:** 2017-08-10 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975010

## Citation

> US National Institutes of Health, RePORTER application 9975010, Mitochondrial ROS and Microglia in Rett Syndrome (5R01HD088832-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9975010. Licensed CC0.

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