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. !

Public Health Relevance

Ataxia-telangiectasia (A-T, an autosomal recessive disease) is a multifaceted incurable progressive disease that ultimately leads to cerebellar degeneration and death of the patient but new clinical data suggest that white matter defects and extensive astrogliosis appear prior to the onset of neuronal degeneration. As studies on glial cells in A-T are largely absent, we have developed a new animal model for A-T that shows glial defects reminiscent of those seen in human disease and have established patient iPSC derived astrocyte cultures that mirror the defects we identified in the mouse model. Using in vivo and in vitro approaches we test the overall hypothesis that glial cells play a critical role in the pathology associated with A-T and offer potential new therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56NS111927-01A1
Application #
10129452
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Zhang, Ran
Project Start
2020-04-01
Project End
2021-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Rochester
Department
Genetics
Type
School of Medicine & Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627