Friedreich's ataxia (FRDA) is an autosomal recessive, inherited neurodegenerative disorder. The signs and symptoms of FRDA are reminiscent of the mitochondrial encephalomyopathies and include progressive ataxia of all four limbs, dysarthria, areflexia, sensory loss, and muscle weakness. Skeletal deformities and cardiomyopathy are found in most patients, impaired glucose tolerance and diabetes mellitus are found in -30% of patients, and reduced visual acuity and hearing loss are occasionally seen. Onset of symptoms usually occurs around puberty and most patients are confined to a wheelchair by their late 20s. Myocardial failure is the most common cause of premature death. FRDA is the most common hereditary ataxia, with a prevalence of approximately 1 in 40,000 in European populations, and there is currently no proven effective treatment. FRDA is caused by mutations in the FRDA gene, which encodes the protein frataxin. Although encoded in the nucleus, frataxin is imported into the mitochondrial matrix. Studies of yeast and murine frataxin homologues, and of patient material, indicate that mitochondrial dysfunction, caused by oxidative damage and concomitant mitochondrial iron accumulation, underlies the signs and symptoms of FRDA. Preliminary studies using simple measures of mitochondrial function in the yeast model system, and in primary FRDA cells, support the feasibility of using a cell-based approach to high-throughput drug screening for FRDA. Hit compounds from such a screen could then be tested in the recently developed mouse models of the disease. The protein targets of hit compounds could be identified using a chemical genetic approach in yeast, allowing further drug development. The overall goal of the proposed research is to identify potential treatments for FRDA.
The Specific Aims are: 1) To develop high-throughput, cell-based drug screening assays for FRDA. Because mitochondrial dysfunction underlies the signs and symptoms of FRDA, our assays will be designed to screen for compounds that improve mitochondrial function. We will use measures of mitochondrial function suitable for a 96-well format, in the yeast model system, and in primary FRDA cells. 2) To develop a chemical genetic screening assay for the identification of drug targets. We will use a colony-color screening technique in the yeast model system to identify the target proteins of hit compounds from our high-throughput drug screening assays for FRDA.
| Cotticelli, M Grazia; Rasmussen, Lynn; Kushner, Nicole L et al. (2012) Primary and secondary drug screening assays for Friedreich ataxia. J Biomol Screen 17:303-13 |
