# Glial Cell function in Ataxia Telangiectasia (A-T)

> **NIH NIH R56** · UNIVERSITY OF ROCHESTER · 2020 · $385,000

## Abstract

Ataxia telangiectasia (A-T) is a lethal multifactorial genetic disease with no cure. The specific mutations in
A-T occur in the ubiquitously expressed gene encoding the Ataxia Telangiectasias mutated (ATM) protein.
While the disease-causing gene has been known for decades, no progress has been made in halting the
cerebellar degeneration that is the most devastating hallmark of A-T. This is mainly due to the fact that animal
models of A-T fail to phenocopy the cerebellar degeneration pathology for reasons that are not known.
 In our proposed studies, we will take advantage of accumulating patient data indicating that regional
demyelination and increased astrogliosis manifest prior to cerebellar degeneration in A-T. These exciting
findings could offer a different insight into new cellular targets of A-T.
 The glial cell compartment has largely remained unstudied in A-T and glial involvement in the neurological
sequelae in this disease is not clear. In this application, we will address the important knowledge gap on the
role of glial cells in A-T and will test the hypothesis that loss of ATM function in glial cells renders them
vulnerable to physiological insults and also impacts their ability to support neural cells.
Our preliminary data show that, unlike cerebellar degeneration, glial defects are conserved in our new
animal model of A-T (referred to as A-T[M]) and appear to be related to the overall oxidative burden known to
occur in A-T. We found that A-T[M] animals showed loss of myelin at baseline and exacerbated demyelination
and impaired remyelination after an oxidative insult. We also found, in A-T[M] animals, defects in astrocytes
and microglia activation both at baseline and after injury. To determine whether the cellular defects we see in
the murine model are relevant for the human disease, we also established human patient iPSC-derived
astrocytes and found conserved defects, raising the possibility that A-T[M] astroglia contribute to a non-
supportive environment for oligodendrocytes and neurons.
 To understand the glial defects in A-T and their possible contribution to neuronal death, we will in Aim 1
characterize myelination at baseline and after injury at various ages. We will use our inducible A-T[M] mouse
model to target loss of ATM to oligodendrocytes (OLs) to determine the contributions of loss of ATM in OLs in
de- and re-myelination pathologies in vivo. Aim 2 will focus on the role and degree of astrocyte dysfunction in
vivo and in vitro through targeted loss of ATM in astrocytes and its impact on de- and re-myelination, and also
will phenotypically analyze astrocytes in vitro exposed to various stressors. In Aim 3 we will test the hypothesis
that astrocyte defects are preserved in human cells, using iPSC technology and in vitro astrocyte analyses.
!

## Key facts

- **NIH application ID:** 10129452
- **Project number:** 1R56NS111927-01A1
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** MARGOT MAYER-PROSCHEL
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,000
- **Award type:** 1
- **Project period:** 2020-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129452

## Citation

> US National Institutes of Health, RePORTER application 10129452, Glial Cell function in Ataxia Telangiectasia (A-T) (1R56NS111927-01A1). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10129452. Licensed CC0.

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