Ataxia UK is funding a project alongside the Spanish organisations R+SCAs (Plataforma de Apoyo a la Investigación de las Ataxias Espinocerebelosas) and ACAH (L’Associació Catalana d’Atàxies Hereditàries), investigating the involvement of DNA repair mechanisms in the modulation of age onset in a range of ataxias. The project is led by Dr Conceiçãon Bettencourt, Prof Henry Houlden, Prof Paula Giunti and Prof Nick Wood at the UCL Institute of Neurology.

We interviewed Wayne Yau, a PhD student at UCL, about his aspirations for the project.

What is your background prior to working on this project?

I am a neurologist who was trained in various hospitals in Australia and at the Royal Free Hospital in the UK. I have a passion for the neurogenetics of movement disorders I am interested in discovery of genetic causes and new therapeutic options for movement disorders, especially in ataxic disorders. How did you get into ataxia research? After my clinical fellowship at the Royal Free Hospital in 2017, I was looking for an opportunity to get involved in research in ataxia. I was excited to see this PhD studentship advertised at UCL, kindly supported by Ataxia UK and others. I met with Professor Houlden and Dr Bettencourt and realised the potential impact this project could have on treatment of patients with spinocerebellar ataxia in the future. I am fortunate to be given this position at the end of 2017. What is it that interests you about ataxia? I have looked after quite a few families with ataxia. You really see the impact ataxia has on the individuals afflicted with this condition. It robs them their ability to move, speak and swallow; in many cases in the prime of their lives. Like many other neurogenetic conditions, there is still no effective disease modifying treatment yet. As a doctor, you often feel helpless, that’s why I like to get involved in research to find an effective therapy for them.

What is the project about?

We are investigating whether genetic differences in DNA repair mechanisms contribute to earlier age of symptom onset in spinocerebellar ataxia (SCA). We are focusing on SCA 1, 2, 3, 6, 7, 17, dentatorubral-pallidoluysian atrophy and spinobulbar atrophy. These disorders are caused by abnormal expansions in certain genes and are otherwise known as polyglutamine diseases. Longer expansions are associated with earlier age at disease onset. A recent study in patients with Huntington disease (also a polyglutamine disorder) and SCAs demonstrated that various components of the DNA repair genes significantly modify age at onset of Huntington Disease and selected SCAs. Larger studies of patients with SCA are required to validate these results and to investigate underlying molecular mechanisms.

What have you achieved so far?

We have collected over 3,733 DNA samples from patients with polyglutamine diseases. They are stored at the Institute of Neurology. I have begun experiments on the samples to confirm the length of their abnormal gene expansions. We aim to enroll 9000 subjects. There is great interest from various SCA study groups/consortiums worldwide who are we are working with to achieve this target. I am also working with clinicians and research groups to collate core and advanced clinical features of these patients. These additional information will allow us to identify genetic variants associated with other important clinical factors such as disease progression or age at death. We aim to extend this study to Friedreich’s Ataxia (FA). FA is also caused by caused by abnormal gene expansions. We currently hold 200 DNA samples from patients with FA at the Institute of Neurology but we are also in the process of securing more samples.

What are you enjoying so far about working on the project?

I have been enjoying working with a large number of collaborators passionate in this area. It is also very inspiring to work with patients who are willing to help make this study possible.

Is there anything that you’ve found challenging?

Some of the neurogenetics laboratory research techniques are new to me. I find it both challenging exciting to learn these new techniques.

What is an average day working on the project like for you?

It is fairly variable. I spend a lot of time contacting potential collaborators and creating a database of existing DNA samples and data. I also spend a couple of afternoons a week in the neurogenetics clinic recruiting patients. The rest of the time I spend in the lab looking for new genetic causes for people with ataxia without a molecular diagnosis.

What are your hopes and aspirations for the project?

I am hopeful that we will be able to identify the key genes responsible for the variations of disease severity in different patients with spinocerebellar ataxia with abnormal gene expansions. This will give researchers new targets for exploring disease modifying treatments. 

Posted on 31/07/2018