Embryonic stem cell models of CAG repeat disease

Nine neurodegenerative disorders are caused by CAG/polyglutamine (polyQ) repeat expansions. The underlying molecular mechanisms responsible for disease specific neurodegeneration remain elusive. In vivo and in vitro models utilizing rodent tissues, immortalized human cell lines, and human post mortem samples have provided insight into disease mechanisms. Concern that cellular and molecular processes observed in these models may not faithfully reproduce human diseases or be useful to identify compounds of therapeutic utility has driven development of new disease models. In addition to their therapeutic potential, stem cells represent a renewable source of tissue that can be directed into neurons and glia and can be used to study neurodegenerative cascades from their inception. Neuronally differentiated human stem cells containing CAG repeat expansions have the potential to accurately replicate human CAG repeat diseases and may be a faithful predictor of which compounds will be of human benefit. As a first step in development of this type of model, we developed murine embryonic stem cell models to study the mechanisms of polyQ tract induced neuronal degeneration.