Jonathan Alexander

Research/Areas of Interest

My studies are defining novel roles of adenomatous polyposis coli (APC) and .-catenin (.-cat) proteins as key regulators of synaptic maturation and plasticity. Human genetic studies show strong correlations between dysregulation of .-cat functions and intellectual disabilities, and APC is the major negative regulator of .-cat.

My work focuses on how up- or down-regulation of .-cat, in vivo, results in pathophysiological changes relevant to learning and memory. I am also identifying new roles for these proteins in regulating neuronal function through interactions with proteins such as the Fragile-X mental retardation protein (FMRP) as a means to regulate signal based mRNA translation at the synapse. The goal of my research is to provide insight into critical pathways as potential therapeutic targets for ameliorating the deficits associated with intellectual disability and autism.

I am also currently working on a new disease model for CTNNB1 syndrome, a monogenic disorder that results in intellectual disabilities and muscular dystonia and spasticity in children. We are testing new generation inhibitors as preclinical proof of principle that increasing beta-catenin back to an effective range will restore the cognitive and muscle deficits we observe in our mouse model. In collaborative efforts with pediatric geneticists and the Simons Foundation, I am also currently working with human IPSCs derived from CTNNB1 syndrome patients. We will differentiate the iPSCs to both neuronal and muscle cells and test the therapeutic effectiveness of the drugs in these preclinical human cell models.