The National Ataxia Foundation (FARA) recently awarded four post-doctoral fellowship grants covering various aspects of ataxia research. Magda Matos Santana at the Center for Neuroscience and Cell Biology, in Portugal, was among the recipients, recognized for her exploration of advanced models based on induced pluripotent stem cells (iPSC) of Machado-Joseph disease (MJD) — a much-needed area of ataxia research.
Machado–Joseph disease (MJD), also termed spinocerebellar ataxia type 3, is the most common type of dominantly inherited ataxias, but is still a rare disease. As with other spinocerebellar ataxias, it is characterized by repeat sequences of three DNA bases CAG, coding for the amino acid glutamine. In MJD, this poly-glutamine mutation causes neurodegeneration of spinal and cerebellar neurons.
Effective therapies for MJD are not available, and research has been hampered by a lack of solid disease models for mechanistic and preclinical studies.
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The advance of induced pluripotent stem cell (iPSC) technology has made it possible to study disease mechanisms in cells holding mutations from individual patients, more closely mimicking cellular processes than could be expected from earlier cellular models.
iPSC, and the tissue-specific cells derived from them, have now become a leading tool in MJD studies, allowing for substantial advances in both the studies of molecular mechanisms contributing to disease and the screening of drug candidates.
Despite such success, an inherent problem with the iPSC approach has been the high variability between lines of patient-derived cells. Experiments have also yielded differences in the development of tissue-specific cells, and the genome of iPSCs has been found unstable.
As a potential solution to these issues, Dr. Matos Santana is working to identify typical signatures associated with disease mutations by comparing iPSCs from patients with MJD and control individuals. The cells from both patients and controls will be selected to hold the same genotype, apart from the disease-causing mutation. This will allow studying the impact of the disease mutation isolated from other cellular processes that might differ due to genomic variability.
“We expect this project can make a truly important contribution to the field of ataxias and particularly of Machado-Joseph disease by providing the models and methodologies to enable significant advances,” Dr. Matos Santana wrote in her proposal to FARA.
The project also aims to develop and implement methods that might be used for medium- or high-throughput screening of specific defects — allowing further study of disease mechanisms and drug screening.