Ataxia UK Research Report 1988 As last year, we supported research into both Friedreich’s and the dominant cerebellar ataxias at the Royal Free Hospital in North London and St Mary's Hospital, Paddington. In the case of Friedreich's Ataxia, our interest is in frataxin, which is a protein. We know that a genetic mutation reduces the amount of frataxin in the cells of people with FA. What we need to know now is: what is the normal function of frataxin? how does the mutation affect the level or function of frataxin? how does frataxin deficiency damage cells? We are fairly sure that frataxin is involved in regulating the amount of iron in the mitochondrion of the cell (the mitochondrion is a small body within the cell which produces the energy that it needs to function). The evidence for this comes mainly from studying yeast cells. But yeast cells are not human cells, and we need to know whether the changes in yeast cells are like the changes in the cells of people with FA. Unfortunately, it is rarely possible to study the role of frataxin directly in living people. Yeast can cast light on what may be happening in human cells, but is too simple an organism to enable us to draw firm conclusions about what is happening in human cells or how the genetic defect may be rectified. We therefore need to develop other approaches, including the investigation of iron levels in tissue samples and cell cultures, and breeding genetically modified mice which mimic the human disease. The research teams at the Royal Free and St Mary’s have been carrying out tests on tissue samples taken from the dorsal root ganglia, heart, skeletal muscle and cerebellum of a number of FA patients and blood and skin cells taken from FA volunteers and grown in the laboratory. Their tests on tissues suggest that what happens in yeast cells closely resembles what happens in human cells. The teams suspect that the loss of frataxin is most likely to result in increased iron accumulation caused by either defective iron regulation or free radical damage. The decreases in energy production and mitochondrial DNA are, on this theory, secondary to those events. This is clearly of vital relevance to developing an effective therapy. The studies of cells grown in the laboratory are not yet complete, but they also suggest that the reduction in energy production is a secondary effect of the other changes that take place in cells with reduced frataxin. Lastly, the Royal Free team has been working with Dr Raffaele Lodi at the John Radcliffe Hospital using Phosphorus Magnetic Resonance Spectroscopy to study the ability of mitochondria in skeletal muscle or heart cells to generate the energy the cells need to function. They noticed a significant reduction in mitochondrial energy production following arm or leg exercise and in the heart muscle of FA patients. This result might be used to assess the value of therapies in the future. The team at St Mary's has been attempting to breed mice (known as mouse models) to throw light on the normal role of frataxin and the result of the mutation. Two models are being bred. The first model will be a mouse which produces no frataxin at all to allow the team to study the role of the gene during the development and maturation of the nervous system and its involvement in maintaining healthy nerve cells. This could be difficult, as everybody, including FA patients, has some frataxin, and a mouse with none at all may be unable to survive. The second model will be a mouse with similar frataxin levels to those in people with FA, created by inserting the human mutation into mouse DNA. When these models have been created, the team hopes to be able to confirm that they show similar clinical features, including iron accumulation, to people with FA. If so, then the way is opened to using the mouse models to evaluate the efficacy or potential toxicity of therapy. The team at St Mary's has also been developing mouse models for autosomal dominant CA. Research into CA is complicated by the fact that 8 different forms of the condition have been identified, labeled SCA1, SCA2, SCA3 etc. Each SCA is due to a mutation on a different gene. Some of the genes have now been isolated. Each gene is likely to have a slightly different function, but they all share a common mutation mechanism, ie the expansion of the CAG repeat motif. Considerable progress has been made in understanding how the expanded CAG repeat causes cell death. Recent studies indicate that it may cause proteins within the cells to aggregate and form unusual deposits within the nucleus. Usually, toxic products are broken down and removed from the cell, but these aggregates are insoluble and resist being broken down. Consequently, their presence increasingly interferes with the normal functioning of the cell, ultimately leading to its premature death. Several mouse models have been generated by other groups, by inserting the repeat motif in isolation but these are not entirely representative. St Mary's have therefore been trying to insert the mutation within the full-length gene for SCA2 and SCA3 (also known as Machado-Joseph disease, which they have been studying for some years). The model will enable the team to show exactly when and how quickly deposition of the aggregates occurs and which nerve cells are primarily affected. This information will be absolutely critical for the future evaluation of corrective therapies, and will provide the benchmark against which they can be judged. Research strategy 1998-99 We shall be reviewing our research strategy during 1998-99 to make sure that we are ready to take part in the clinical trials that we expect to start in the next few years. We particularly want to ensure that the UK plays a leading part and that advances are accessible to people here at the earliest opportunity.