Research Grant

Patricia Maciel, PhD

University of Minho, Campus de Gualtar, Portugal
Identification of compounds that modulate ataxin-3 aggregation and neurological dysfunction in a C. elegans model of Machado-Joseph disease.

Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3, is caused by mutations in the protein ataxin-3 that make this protein prone to aggregate and toxic to specific groups of neurons. This leads to the progressive neurodegeneration and to the typical symptoms of MJD: ataxia and severe limitations in eye movements among others. Currently there is no effective treatment for this disorder. Our goal is to test a large number of commercially available chemical compounds as potential therapies for MJD. For this, we will use a model of the disease in the worm C. elegans, which in spite of being a very simple animal possesses a very well characterized nervous system, is quite well characterized at the genetic level, is transparent - allowing monitorization of events within the neurons in the live animal, and, unlike mouse models, is amenable to large scale drug studies. This model, which has been generated in our lab, expresses the mutant human protein in its nervous system and replicates important features of the disease, such as the aggregation of ataxin-3 and a neurological impairment of the animals (including abnormal movement). We will use it to screen a panel of off-patent and FDA approved compounds, selecting those that, while not toxic to the animals, prove to reduce ataxin-3 aggregation and/or to improve the worms’ neurological phenotype, i.e. improve their motility. These compounds will provide good candidates for testing in mouse models and eventually for future clinical studies.