Young Investigator for the SCAs Award

Thorsten Schmidt, Ph.D.

University of Tuebingen, Germany
Isoforms and polymorphisms of Ataxin-3 as modifiers of the pathogenesis in Spinocerebellar Ataxia Type 3

Spinocerebellar ataxia type 3 (SCA3) or Machado-Joseph disease (MJD) is caused by the expansion of tandem repeat of the three DNA elements CAG within the so called ataxin- 3 gene. This means that everybody in the general population has between 12 and 40 repetitions of CAG in one’s own ataxin-3 gene. SCA3 patients, however, have more than 62 of these CAG repeats. Everybody has two copies of the ataxin-3 gene, one inherited by the mother, one inherited by the father. In most cases, only one of these two copies contains the expanded CAG repeat and the second copy contains a CAG repeat in the normal size range.

Statistically, more repeats lead to an earlier onset of symptoms while patients with less repeats get first symptoms at much older age. However, this is a statistically correlation and it is not possible to predict the exact age at onset from just the number of CAG repeats. For examples, a SCA3 patient with 71 CAG repeats may get first symptoms as early as with 25 years or not until 60 years of age. In order to improve the prediction when first symptoms may occur, we analyzed in more than 500 european SCA3 patients whether additional variation of the ataxin-3 gene –beside the CAG repeat– influence the age at onset. We observed that each patient has a specific combination (a so called haplotype) of these different variants both in the normal and the expanded ataxin-3 copy. Interestingly, 2 % of the European patients with one specific haplotype had a much later (5 years later) onset of symptoms.

Within this project, we want to find out why the patients with this specific haplotype develop first symptoms five years later. What is so different in these 2 % of patients? Why do they get first symptoms much later? Is it the copy with the normal CAG repeat which modifies the disease? Or are these additional variations we analyzed in the expanded allele responsible? We will try to replicate the situation present in these patients in our lab in order to answer these questions. Our project will help understanding the processes which lead to SCA3, may lead to a better prediction of the age at onset and may point to novel strategies for a possible future therapeutic intervention.