YOUNG INVESTIGATOR Award

Leeanne McGurk, PhD

University of Pennsylvania, Philadelphia, PA
The identification of putative drug targets for SCA3 using Drosophila melanogaster

The cerebellum, which is found at the back of the brain, is the major center for motor control. Patients that suffer from degeneration of the cerebellum show a progressive loss of motor control and balance. This symptom, called ataxia, is observed in many neurological diseases that include the spinocerebellar ataxias (SCA). There are around thirty different subtypes of SCA, each of which are due to distinct mutations. Of the thirty SCA3 is the most prevalent. Therapeutic strategies to prevent the degeneration in SCA patients have proven unsuccessful. Due to the nature of the mutation, which is present in the ataxin3 gene, designing a good strategy is difficult. There are many proteins that ATAXIN3 effects and strategies have so far targeted some of those proteins. Unfortunately the results generated by clinical trials contradict each other and no strategy, as yet, has proven to be 100 percent successful. In order to identify new drug targets for SCA3 the mechanisms by which mutant SCA3 confers toxicity needs to more greatly understood. We aim to reveal new genes (potential drug targets) that generate ataxia. To do this we will use the fruit fly. It has been well established that mutant ataxin3 can
cause degeneration of the fruit fly eye and our preliminary data suggests that mutant ataxin3 can also cause an ataxia-like behavior in flies. We want to determine which of the proteins that ATAXIN3 interacts with causes the ataxia-like behavior. There are approximately 650 proteins
that directly interact with ataxia causing proteins and ataxia associating proteins. We have found that 200 of these genes are present in Drosophila. We will prevent the proteins from being made in the ataxia-causing neurons and we will assess whether the flies suffer from ataxia. We aim to show that these proteins can prevent the ataxia-like behavior in the SCA3 model by increasing the amount that is present in the brain. We will not only do this in the SCA3 fly model but also in the fly models of other neurological diseases such as Friedreich's ataxia. Finally we want to
screen a database of drug molecules that have the ability to increase the amount of our candidate proteins, and test whether they will be suitable therapeutic strategies by feeding them to our SCA3 fly model. As well as providing insight into the mechanisms involved in the progression of SCA3 the findings of this project can directly translate into data that is beneficial to clinical advancement of the disease.