What happens to neurons in disease?

During neurogenesis in all animals, neurons are generated from neural stem cells and progenitor cells. The molecular and genetic factors influencing neurogenesis have been elucidated in detail and notably involve the Notch pathway and genes linked to regulation of this pathway. Also, prior to neurogenesis, genes implicated in neuronal function are repressed through a number of factors including primarily the REST protein. All neurons are understood to be “post-mitotic”. The central question that arises in neuronal pathologies is what happens to these neurons? Through a combination of stem cells derived from subjects with distinct diseases of the brain including Alzheimer’s disease and glioblastoma, high throughput transcriptomic measurements, and a host of phenotypic measurements, we have uncovered surprising and interesting mechanistic origins underlying several neural pathologies. De-differentiation and reintroduction of cell cycle appear as common mechanisms that affect neurons triggered by changes in chromatin topologies. In this talk, I will discuss our results and provide insights into the question of what happens to neurons in these diseases and explore strategies that can be used to reverse these altered causal mechanisms.