Sunday, May 11, 2025
5/11/2025
MOLECULAR PATHOGENESIS STUDIES OF RETT SYNDROME - Project Summary Rett syndrome (RTT) is a severe neurodevelopmental disorder with postnatal onset. Caused by loss-of-function mutations in the X-linked gene methyl CpG binding protein 2 (MECP2), girls with classic RTT develop normally for the first ~12-18 months of life, reaching the expected milestones, but then lose their acquired skills over a period of weeks and instead develop stereotypies, ataxia, apraxia, seizures, and a host of other symptoms. Milder mutations that primarily reduce the amount of MeCP2 protein produced cause milder symptoms that take longer to manifest. Various mouse models of RTT (male Mecp2 nulls, female heterozygotes, mice bearing specific disease-causing mutations) faithfully reproduce this natural history (normal health, regression, and deterioration). Strikingly, deletion of the gene in adulthood reproduces the full phenotype, whereas expression of Mecp2 in adult null mice rescues it, demonstrating that MeCP2 has some as- yet-unspecified function that is critical for neuronal maintenance. Although gene therapy would seem the best hope, the mosaic nature of MeCP2 in females (~50% of neurons will have wild-type MeCP2) presents a difficult challenge for this approach, as too much MeCP2 also causes disease (MECP2 duplication syndrome [MDS], which is every bit as devastating). Therefore, in our search for viable therapeutic options, we are guided by two principles: the period of early normal development provides a window of opportunity to intervene and delay onset, and the lag between loss of MeCp2 and appearance of symptoms (or reversal of symptoms, in the context of rescuing MDS) means there is a cascade of molecular events that, if we could but map them, should allow us to identify key genes or pathways that could serve as therapeutic targets and biomarkers of treatment response. Having previously found that forniceal deep brain stimulation improves learning and memory in RTT mice, we hypothesized that motor training during the presymptomatic period might also stimulate the neural circuits and delay symptom onset. Indeed, this proved to be the case. We now seek to trace the cascade of molecular and cellular changes that occur after MeCP2 depletion but before the onset of symptoms to define initiators of RTT pathogenesis and biomarkers of response as we stimulate the brain through intensive training or raise MeCP2 levels in the context of hypomorphic mutations. In our first aim, we will identify the transcriptional changes that take place in task-specific neurons that respond to intensive training with improved function, electrophysiology, and morphology. In aim 2, we will trace the cascade of molecular, epigenetic, and cellular changes that follow for several weeks after acute MeCP2 depletion, and that eventually lead to neurological dysfunction. In aim 3, we will upregulate MeCP2 levels in two distinct RTT mouse models, each carrying mutations that reduce MeCP2 levels, to determine the extent of improvement.
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