POST DOCTORAL RESEARCHER The Florey Institure of Neuroscience and Mental Health Melbourne, Victoria, Australia
Abstract: Motor neuron disease (MND) is a progressive neurological disorder, marked by the degeneration of upper motor neurons in the spinal cord as well as the cortex, with no known cure. Recent research has implicated a role for inhibitory neurons within the cortex in modulating disease progression within the excitatory motor neurons. To better understand disease progression and unravel potential disease initiating mechanisms in MND, our lab has developed new methods for differentiating human pluripotent stem cells (PSCs) into specific neural subtypes, including cortical interneurons (inhibitory) and layer V cortical projection neurons (the laminar population predominantly affected in MND). Here we have established a 2D co-culture system that combines these differentiated neurons using diseased or control iPSCs carrying mutations in the C9orf72 gene, the most common genetic mutation in familial MND. This model allowed the study of both histological, biochemical and functional changes in both neural subtypes and further investigate the role of interneurons in MND pathology. Our findings show that exposure to chemical stressors leads to an increase in reactive oxygen species, axonal fragmentation, stress granule formation and neural activity in both mutant interneurons and projection neurons. Notably, these pathological changes are more pronounced when mutant and isogenic projection neurons are co-cultured with mutant interneurons. Ongoing work is probing transcriptional and electrophysiological changes in these cultures. These results underscore the importance of including specific and disease-relevant neural subtypes to accurately model MND in vitro and highlight a potential regulatory role of cortical interneurons in MND pathology.
