DNA Damage Response and Repair, DNA Methylation, and Cell Death in Human Neurons and Experimental Animal Neurons Are Different.

Abstract

Neurological disorders affecting individuals in infancy to old age elude interventions for meaningful protection against neurodegeneration, and preclinical work has not translated to humans. We studied human neuron responses to injury and death stimuli compared to those of animal neurons in culture under similar settings of insult (excitotoxicity, oxidative stress, and DNA damage). Human neurons were differentiated from a cortical neuron cell line and the embryonic stem cell-derived H9 line. Mouse neurons were differentiated from forebrain neural stem cells and embryonic cerebral cortex; pig neurons were derived from forebrain neural stem cells. Mitochondrial morphology was different in human and mouse neurons. Human and mouse neurons challenged with DNA-damaging agent camptothecin showed different chromatin condensation, cell death, and DNA damage sensor activation. DNA damage accumulation and repair kinetics differed among human, mouse, and pig neurons. Promoter CpG island methylation microarrays showed significant differential DNA methylation in human and mouse neurons after injury. Therefore, DNA damage response, DNA repair, DNA methylation, and autonomous cell death mechanisms in human neurons and experimental animal neurons are different.