Research Project information

Principal researcher: Dr John Reynolds and Professor Grant Stewart
Institute:  University of Birmingham
Cost:   £105,183.46 over 36 months
Project Completion Date: October 2023

Project Overview
Individuals with Ataxia-Telangiectasia (A-T) and the related disorder Ataxia-Telangiectasia-Like Disorder (ATLD), which are caused by mutations in the ATM gene and MRE11 gene respectively, suffer from progressive degeneration of the cerebellum (the region of the brain that is responsible for coordinating voluntary muscle movements and regulating balance). The aim of this project was to gain a further understanding of DNA repair deficiencies and neurodegeneration and to try and pinpoint what type(s) of DNA damage are involved.  The original hypothesis was that the cerebellar degeneration in A-T and ATLD is caused by a failure to repair TOP2 associated DNA double strand breaks which ultimately results in neuronal cell death within the cerebellum, leading to clinical features of loss of balance and deterioration in fine motor control.

Research Methods and Outcome
A unique ATLD patient with a mutation in the Mre11 protein was studied in this project to understand the cellular processes in cell death in the cerebellum in more detail.

The team acknowledged at the outset this is basic research and therefore would not have a medium- or short-term impact on individuals and families affected by A-T / ATLD.

The project had the following objectives:

1a) Identify and characterise the cellular defect/s present in ATLD cells with the MRE11 mutation.

1b) Investigate the cellular defects in 15 ATLD cell lines

  • Investigate the impact of the pM26T mutation on MRE11 function.
  • Define the nature of the TOP2 DSB repair defect in cells carrying the mutation.

The first objective demonstrated that the inability in the ATLD patient to repair DNA damage in the presence of the MRE11 mutation was not due to defects in ATM activation.

Secondly, in the 15 ATLD cell lines available the team have demonstrated that inability to activate ATM is not a common cellular phenotype in ATLD.

The pM26T mutation was not shown to have any deleterious effect on its ability to activate ATM. However, this may have been due to the techniques used and work is ongoing to modify this.

The team found no evidence that the ATLD cells expressing the mutation demonstrated any defects in the repair of DNA breaks. Work is ongoing on this third objective.

Although the initial hypothesis was disproved, this research has delivered some useful information which could be built into future projects. Some work is still ongoing and therefore there are no current plans to publish.