Effects of Re-expression of Motor Neuron Selector Transcription Factors on ALS Pathology

The fact that young neurons are impervious to mutations that cause late-onset neurodegenerative diseases highlights the critical role of aging in disease etiology. Recently we established that spinal motor neurons undergo a complex maturation program in postnatal mice during which genes encoding the proteasome and chaperonin complex are downregulated, suggesting that motor neurons become less adept at managing and degrading misfolded proteins over time. We hypothesize that these gene expression changes underlie the increased vulnerability of adult motor neurons to mutations causing amyotrophic lateral sclerosis (ALS). To test this hypothesis, we will re-express the embryonic motor neuron selector transcription factors ISL1 and LHX3 in postnatal motor neurons in mouse models of ALS in vivo and in iPSC-derived ALS motor neurons in culture. We will examine the effects of ISL1 and LHX3 re-expression on early and late pathologies observed in ALS mouse models and on motor neuron survival in response to proteostatic stress in vitro. We will also evaluate changes in gene expression, chromatin binding and accessibility, and DNA methylation. Jointly these studies will provide new insights into the effects of heterochronic expression of embryonic selector transcription factors on mature neurons, and explore their therapeutic potential.