Understanding ataxia

Research focus: Cerebellar ataxia is a condition which affects some 10,000 adults in the UK, causing problems with movement, motor coordination, balance and speech. As our population increases, the numbers suffering from ataxia look set to rise. Wadham Junior Research Fellow Esther Becker is working to understand the genetic and molecular mechanisms that lead to brain disorders such as ataxia.

Esther Becker

As her latest findings are published in the Journal Movement Disorders this week, Esther explains her research.

As a PhD student at Harvard University, Esther studied cell death in the brain using cells from the cerebellum as her model. This led to an interest in the cerebellum itself as she realised how little we know about this part of the brain and the diseases associated with it. The cerebellum (Latin for "little brain") is a region of the brain that plays an important role in the control of motor functions. The cerebellum does not initiate movement, but it significantly contributes to coordination, precision and accurate timing. Cerebellar damage produces disorders in fine movement, equilibrium, posture and motor learning. Interestingly, recent research has shown that the cerebellum is also involved in many higher cognitive processes such as language, emotion and social skills.

Ataxia is a neurodegenerative disorder, similar to Parkinson’s or Alzheimer’s, where, as one grows older, you have a loss of nerve cells resulting in problems with movement, motor coordination, balance, and speech. Although there are some congenital forms of ataxia and childhood onset ataxia, cerebellar ataxia usually results from progressively dying nerve cells in a normally developed cerebellum.

Understanding the genetic and molecular causes of ataxia is part of Esther’s work. “Ataxia can have many different causes – infections, tumours, chronic alcohol abuse, as well as family history,” she explains. “Scientists have identified at least 50 genetic forms (in dominant and recessive genes) of ataxia and that is just the tip of the iceberg. There are probably many more genes awaiting discovery, and we are very interested in studying those.”

To carry out her research, Esther and her group are currently using several different model systems. She explains: “We work with immortalised human cells in culture (cells which never stop dividing) and we can also culture nerve cells from the mouse brain and study them. We also study the intact brain in a mouse, can do histology where we section the brain, look at its structure and we can look at behaviour and see how a mouse with ataxia reacts.”

More recently, Esther has become interested in utilizing human induced pluripotent stem cells (iPSCs) to study the development of human cerebellar nerve cells from healthy individuals as well as patients with cerebellar diseases in the dish. Working with the Oxford Stem Cell Institute they are reprogramming skin cells into iPSCs to ultimately create cerebellar neurons (nerve cells), a model which Esther hopes will be in use within a year.

Says Esther: “We are working to identify the genes effected in ataxia, to see how mutations in these genes affect the cerebellum. We can introduce the same mutations that we know cause the disease in humans into mice and study these as a disease model. We have also taken the reverse approach, studying mice that have ataxia, found the faulty gene which causes the disease, and then looked to find the same genetic mutation in humans. Having screened human ataxia patients we have recently been successful in finding the first human mutation in the TRPC3 gene, which we had previously identified in an ataxic mouse model.”

The research goes further. Having identified the gene mutations for ataxia, Esther’s team has looked at the functions of these genes in cerebellar nerve cells to see exactly what happens when you have a mutation in a particular gene. This involves dissecting the molecular mechanisms of the cells to see what networks the proteins are involved with and how these networks regulate cellular processes. Esther clarifies: “We know all these genetic mutations cause cerebellar ataxia so one idea is that even though you have lots of different gene mutations, the affected proteins might work together in the same cellular networks and pathways. If this is true it could be important for the development of therapeutics which could treat several forms of ataxia, rather than different treatments for every single genetic variation.”

“I am hopeful that we will find and explore these important networks or signalling pathways in cells that are affected by different gene mutations or environmental factors and that we find a way of targeting and treating them. Although we are a long way off finding a cure it is very reassuring for patients to know exactly what is wrong with them and I am hopeful that our findings will help people to have a genetic diagnosis – to find out what kind of mutation they have. Our ultimate goal is to advance our understanding of the genetic and molecular disease mechanisms so that we and others can come up with treatments to help those that suffer from ataxia” says Esther.

Work in The Becker Group is funded by The Royal Society, The Wellcome Trust, the Simons Foundation Autism Research Initiative, the Oxford Stem Cell Institute and the John Fell Fund.