The Neurodevelopmental Consequence of Genomic Stress

The abnormal accumulation of DNA damage in neurons is a shared pathological feature among neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease) and it is also correlated with normal aging. Transgenic mouse models further demonstrate a specific requirement for DNA repair during neurogenesis. It is also known that genomic stress, arising from ongoing transcription and metabolic byproducts, plays a role in aging because it contributes to the accumulation of DNA damage. Previously, studying aging in the human brain has been incredibly challenging; post-mortem tissue is difficult to acquire and is not amenable to longitudinal studies. Furthermore, studies of aging have typically looked at model organisms later in life, meaning that few have assessed how stress exposure impacts the development of the brain and how that ultimately affects the aging process.

With the development of human-induced pluripotent stem cells (hiPSCs), we now have an in vitro model of human neurodevelopment that provides a tool to study models of normal and pathological neurodevelopment. In this study we determine how genomic stress and subsequent DNA damage alters the cell fate of hiPSC-derived neural progenitor cells (NPCs) and their progeny. Our work examines how NPCs respond to genomic stress and whether that response differs from isogenic astrocytes. NPCs are particularly susceptible to transcription associated genomic stress; showing an increase in DNA Double-Strand Breaks, p53 phosphorylation, and alteration in NPC fate decisions. Ongoing experiments will examine how p53 mediates NPC fate decision and alters neuronal diversity during neurogenesis. hiPSC-based neurogenesis provides a human model system to understand genomic stress related mechanisms in aging and neurodegeneration. Defining how neurodevelopmental stress impacts neuronal diversity and DSB burden in early neurons may reveal subsets of neurons predisposed for later neurodegeneration.