This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This is a two-year fellowship from the International Rett Syndrome Research Foundation to define the involvement of a gene termed FXYD1 in the neuropathology of Rett syndrome (RTT). RTT is a disorder of brain development that becomes clinically evident 8-18 months after birth. Most RTT patients carry a defective gene called MECP2. This gene encodes a protein that normally """"""""silences"""""""" other genes. Identification of these genes is important, as it may allow researchers to devise therapeutic strategies to treat the disease. Dr. Matagne's studies showed that the brains of RTT patients, and that of mice lacking MeCP2, express more of the FXYD1 gene, which encodes a protein regulating cell excitability. The FXYD1 gene is repressed by MeCP2 in some brain regions such as the frontal cortex;in the absence of MeCP2 the FXYD1 gene is activated resulting in loss of a cell membrane-bound enzyme activity essential for brain cells to recover after responding to other neurons. This fellowship funds Dr. Matagne's salary for her to test this hypothesis that an excess of FXYD1 contributes to the neuropathology of RTT by using mice that are deficient in MePC2, but are unable to produce FXYD1. The results obtained showed that behavioral, electrophysiological and neuronal morphological abnormalities displayed by animals lacking MeCP2 are ameliorated by genetically preventing the FXYD1 response to MeCP2 deficiency, suggesting the possibility of using FXYD1 antagonists as therapeutic agents for the cure of Rett Syndrome.
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