Project 464552

MeCP2 was discovered in 1992 as a protein that binds, reads, and interprets genomic modifications. Such modifications dictate what genes should be turned "on or off" in our body. Later studies showed that MeCP2 regulation and function are critical for brain development and function. MeCP2 is an important protein, and its mutation (interruption) leads to Rett Syndrome (RTT). RTT is a severe neurodevelopmental disorder in young children. RTT patients appear normal at birth, but by 6-18 months of age, they show developmental regression, loss of speech and purposeful hand usage, as well as breathing problems. RTT patients also show neurological symptoms, including seizures, anxiety, and mental disability. Currently RTT has no cure, and its mechanism of disease is not fully clear. MeCP2 mutation in RTT is perhaps the most solid genetic link with mental disability and impaired brain function. Accordingly, mis-regulation of MeCP2 is also associated with Autism Spectrum Disorders (ASD) and Fetal Alcohol Spectrum disorders (FASD). For over a decade, my lab has studied RTT mechanism of disease in murine and human model systems. With support from RTT parents from across Canada and RTT-supported organizations, we have established a unique resource of post-mortem human RTT patient brain tissues in Canada, initiated through direct organ donation by RTT family members. In this application, we propose to perform side-by-side molecular and cellular studies to determine the shared anomalies of the human and murine RTT brains (Aim 1). Next, we will aim to investigate the rescue and recovery of the identified RTT-associated abnormalities, by the application of commonly used drugs in pre-clinical therapeutic studies in RTT mice (Aim 2). Our results are expected to pave the way for designing effective therapeutic strategies in the future that are not only important for RTT, but also for other MeCP2-associated disorders that have no cure or effective treatment.