Does irregular repair of DNA damage in Neurons and Lymphocytes cause cellular degeneration in A-T patients?

Research Project information

Principal researcher: Dr Jean-Pierre De Villartay
Institute: The IMAGINE Institute for Genetic Diseases, Paris
Cost: £65,000 over 12 months
Start Date: 1st of February 2020 (no cost extension until 30th June 2021 agreed January 2021)

What are the researchers proposing to do?
The ATM protein is one of the critical components necessary for the repair of DNA damage in human cells. In patients with A-T, who have mutations in the ATM gene, cells of the brain and the immune system are both affected (called neurons and lymphocytes, respectively). One important aspect of A-T is the progressive nature of these clinical symptoms, which suggests that “time” is a critical factor. It was recently shown that DNA damage may be triggered in neurons, and possibly white blood cells, in the course of normal cellular activities. Dr Jean-Pierre De Villartay and his team will test their idea that the abnormal repair of such DNA damage, especially on a recurrent basis, may explain the progressive cellular degeneration seen in A-T patients. This will be studied in the test tube using cells from human A-T patients and mice with A-T.

It is not fully understood why A-T is a progressive disease (both in the brain and the immune system). Dr De Villartay’s studies on ATM-deficient nerve cells and white blood cells have the potential to help understand the clinical symptoms. In some rare cases, patients with ATM mutations have only mild clinical symptoms in adulthood. Understanding how the pattern of disease relates to specific ATM mutations may help us predict what the future holds for new patients.

How will the research be done?
The project has two aims:

Aim1: ATM deficiency and neurodegeneration:  In this part of the project, the team will investigate how ATM deficiency affects live neurons responding to repeated activating signals in the test tube. They will first map out the precise pattern of DNA damage that occurs across the genome of nerve cells in response to a repeated signal. Then they will compare how faithfully DNA damage is repaired in the presence or absence of ATM.  The team will also measure the impact of accumulated damage on how easily the cell can access the information contained in DNA (“genes”).

Aim2: ATM deficiency and immune function. Based on what happens inside neurons, Dr Villartay and team suggest that lymphocytes might also undergo DNA damage in the course of their normal activities. This is a new idea that can be tested in a similar way to Aim1, but with signals that activate lymphocytes. These cells will be obtained from both A-T patients and mice with A-T, and compared with healthy cells for the pattern of DNA damage and associated changes in gene function.

How could it make a difference to the lives of those affected by A-T?
This project looks at very basic scientific questions aimed at increasing our knowledge of how ATM deficiency leads to the disease A-T. However, it’s possible that insights into the impact of various different ATM mutations on cellular degeneration will help predict the clinical progress of patients early in the disease.