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Understanding the mechanisms of A-T

Understanding the mechanisms of A-T

While massive strides have been made in recent years in our understanding of A-T, there are still many things that we do not understand. While we know that having A-T means that cells cannot produce ATM protein, and we have a greater understanding of the complex role that ATM plays in the cell and its processes, we still do not know why this leads to some of the major symptoms of A-T.

Understanding the mechanisms underlying the development of AT is one of the priority areas for our research strategy. This is essential if we are to be able to develop effective treatments.

There are many ways that we can look to do this. New generations of scanners such as MRI can help us see what is happening inside the body. A better sharing of data and studies looking at how symptoms in individuals develop over time is also important. Then, there is much to learn about some of the less well known aspects A-T such as endocrine disorders, the links to diabetes, premature aging and osteoporosis.

In recent years communication and the sharing of information in the A-T field has improved significantly helped by the A-T Clinical Research Network and the series of biennial A-T Clinical Research Conferences. These were set up by the A-T Society in 2012 and are run by us in partnership with the A-T Children’s Project.

Data gathering and Natural History

A very good way of understanding a condition is to bring together detailed information from a lot of people with the condition

 

Neurodegeneration

Progressive loss of movement, co-ordination and control of gait in A-T children is caused by loss of cells in the cerebellum, particularly Purkinje cells, and shrinkage. Other types of movement disorder common in A-T, such as the jerky movements, tremors and dystonia (stiffness) are associated with other parts of the brain.

However we do not understand why it is that Purkinje cells die off in the absence of ATM, when other cells don’t. There are various theories for this, given that ATM seems to be involved in so many different processes within the cell. Some of the better known are:

  • Poor repair of DNA damage. Purkinje cells are known to be very active in transcribing DNA, which often produces breaks in DNA. In the absence of ATM, this damage cannot easily be repaired leading to cell-loss.
  • A number of normal cell processes produce oxygen-based compounds (free radicals and peroxides). If allowed to build up, these compounds can damage the cells – this is called oxidative stress. ATM is known to play a role in dealing with oxidative stress so it is likely that the cells of people with A-T are at much greater risk of this. Purkinje cells, being particularly active would be all the more at risk.
  • Mitochondrial dysfunction. Mitochondria are individual units within the cell which provide energy to the cell – and produce compounds which contribute to oxidative stress. There is evidence that ATM plays a role in regulating mitochondria, so its absence could lead to an increase in oxidative stress, which as outlined above cannot be dealt with effectively.
  • Problems with regulating histones and chromatin, the structures around which DNA is organised, which in turn lead to problems in transcribing and regulating genes.

However, as yet we do not know whether one of these is critically important or whether it is a combination of all of them. It would be extremely helpful though if we were able to clarify this. If we knew that we were trying to act on a particular process or pathway we could more easily identify drugs that might be helpful.

Brain imaging

Imaging offers a way to try and understand what is happening inside the living brain. A number of different projects are using MRI imaging to look at the brains of people with A-T and compare them to ‘controls’ who don’t have A-T.

The CATNAP project (Children’s Ataxia Telangiectasia Neuroimaging Assessment Project) uses the latest magnetic resonance imaging (MRI) technology to reveal the processes underlying the neurological symptoms in A-T. A key aim of the study, led by Dr Rob Dineen, is to identify bio-markers. These are biological indicators which can be measured and show the progress of a biological process, in this case the progress of the neurological problems in A-T. In doing this the study hopes also to throw light on the processes that are taking place in the brain. Find more information here (link).

Stephen Rose and his team in Brisbane used diffusion magnetic resonance imaging (dMRI) to carry out a study which showed significant white matter degeneration along the entire length of motor circuits, highlighting that ataxia–telangiectasia gene mutation impacts the cerebellum and multiple other motor circuits in young patients.

The team at Johns Hopkins published a study of MRI imaging of 10 adults with A-T which suggested extensive telangiectasia and other vascular abnormalities in adults with A-T, which did not however appear to cause other symptoms.

As technology improves we are likely to be able to gather more information, not just from studies to come, but potentially by reanalysing data from existing projects. This is an area of considerable potential for understanding neurodegeneration in A-T.

Lung imaging

MRI has in the past been more effective in looking at the brain than at the soft tissues of the lungs. However advances in technology mean that this is now becoming possible. Dr Andrew Prayle and Dr Jayesh Bhatt at the University of Nottingham are now embarking on a study using Oxygen Enhanced Magnetic Resonance Imaging to measure lung health over time for a group of children. This will tell us if these tests are reliable in children with AT, and if they are suitable measurements of lung health that could be used in future trials.