Therapeutic strategies for offsetting Neurological Sequelae in A-T

Research Project Information

Principal researchers: Dr. Margot Mayer-Proschel
Institute: University of Rochester, United States of America
Grant award: Funded in partnership with the A-T Children’s Project
Project completion date: July 2015

Project Overview

Ataxi Telangiectasia (A-T) is caused by faults in a gene called ATM (Ataxia Telangiectasia Mutated), which results in the ATM protein not functioning correctly. A range of symptoms are observed, including an increased likelihood of developing cancers and the loss of muscle coordination (ataxia) due to damage of nerve cells (neurons) within the brain. For new therapeutic strategies to be developed, it is crucial that the mechanisms responsible for symptoms are identified and studied. Dr. Mayer-Proschel’s research team aimed to characterise a newly developed A-T mouse model, which lacks a functional ATM protein.

Project Outcome

Dr. Mayer-Proschel’s research teams study of the new mouse model, called A-TMMP, provided a number of surprising and novel findings. For instance, previous reports suggested that the complete loss of the ATM protein would result in more oxidized cells and induce the onset of cancer, and severe defects within the brain. However, A-TMMP cells were not oxidized and the mice only rarely developed cancer. Furthermore, no substantial cellular damage was observed in the cerebellum region of the mice’s brains, reflected by the absence of ataxia. Overall, these results indicate that the loss of the ATM protein does not necessarily result in oxidized cells. This finding is in contrast to previous reports and suggests the importance of genetics in determining the frequency of tumor development and severity of neuron damage.

In addition to the above work, Dr. Mayer-Proschel’s research team studied an alternative mouse model called A-TAWP. Remarkably, they discovered a cellular defect that has also been found in human tissue from an A-T patient. This defect prevented astroglia cells from supporting neuron survival and outgrowth in the cerebellum. Correction of the defect was sufficient to rescue neurons. This suggests that astroglia dysfunction may precede neuron damage in A-T patients.


  • Campbell, A.; Krupp, B.; Bushman, J.; Noble, M.; Pröschel, C.; Mayer-Proschel, M.; A Novel Mouse Model for Ataxia-Telangiectasia with a N-terminal Mutation Displays a Behavioral Defect and a Low Incidence of Lymphoma but No Increased Oxidative Burden. Human Molecular Genetics 2015, 24 (22), 6331- 634
  • Campbell, A.; Bushman, J.; Munger, J.; Noble, M.; Pröschel, C.; Mayer-Proschel, M.; Mutation of Ataxia-Telangiectasia Mutated is Associated with Dysfunctional Glutathione Homeostasis in Cerebellar Astroglia.Glia 2015, accepted for publication (in press)

What Next?

The new mouse model developed provides exiting opportunities for identifying and studying A-T symptoms that are not a consequence of oxidative changes. Future work by the research group will also focus on identifying drugs that can correct the astroglia cell defect in A-T patients. This is a significant first step towards preventing neuron damage in A-T patients.