"Capturing Neurodegenerative Disorders in Patient-Derived Neurons via MicroRNA-Mediated Direct Neuronal Reprogramming"

Andrew Yoo, Ph.D. Associate Developmental Biology Professor Washington University School of Medicine Abstract Yoo Lab researchers study neurogenic activities of microRNAs (miRNAs) and develop cellular reprogramming approaches to turn human fibroblasts directly to neurons without going through stem cell stages. Of particular importance for modeling late-onset disorders, direct neuronal conversion propagates cellular age stored in starting fibroblasts to generate human neurons that mimic the neurons of adult individuals. The miRNA-mediated conversion process relies on the activity of neuronal miRNAs, miR-9/9* and miR-124, that exert reprogramming activities by targeting chromatin remodeling complexes and anti-neurogenic genes, leading to extensive chromatin reconfiguration. The miRNA-induced neuronal state becomes responsive to additional inputs from transcription factors allowing the conversion specifically to disease-relevant neuronal subtypes. Using this strategy, Yoo Lab researchers implement patient-derived striatal medium spiny neurons to model Huntington’s disease and study pathogenic mechanisms underlying the adult-onset neurodegeneration of the disorder, as part of the Progress in Neuroscience Seminar (PINS) series. Publications Cates K*, McCoy MJ*, Kwon JS*, Liu Y*, Abernathy DG, Zhang B, Liu S, Gontarz P, Kim WK, Chen S, Kong W, Ho JN, Burbach KF, Gabel HW, Morris SA, Yoo AS. Deconstructing Stepwise Fate Conversion of Human Fibroblasts to Neurons by MicroRNAs. Cell Stem Cell. 2020 Sep 17:S1934-5909(20)30411-2.Victor, M.B., Richner, M., Olsen, H.E., Lee, S.W., Monteys, A.M., Ma, C., Huh, C.J., Zhang, B., Davidson, B.L., Yang, X.W., Yoo, A.S. Striatal neurons directly converted from Huntington’s disease patient fibroblasts recapitulate age-associated disease phenotypes. Nature Neuroscience. 2018. 3:341-352 doi: 10.1038/s41593-018-0075-7.Yoo, A.S.*, Sun, A.X., Li, L., Shcheglovitov, A., Portmann, T., Li, Y., Lee-Messer, C., Dolmetsch, R.E., Tsien, R.W., and Crabtree, G.R.* MicroRNA-mediated conversion of human fibroblasts to neurons. Nature. 2011. 476, 228-231.