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ASCL1-mediated direct reprogramming: converting ventral midbrain astrocytes into dopaminergic neurons for Parkinson's disease therapy
Sang Hui Yong 1 (Graduate student), Sang-Mi Kim 2,3 (Research worker), Gyeong Woon Kong 1 (Graduate student), Seung Hwan Ko 1 (Graduate student), Eun-Hye Lee 4,5 (Research worker), Yohan Oh 6,7,8 (Professor), Chang-Hwan Park 1,2,* (Professor)
1Graduate School of Biomedical Science and Engineering and 2Hanyang Biomedical Research Institute, Hanyang University,
3Center for Embryo and Stem Cell Research, CHA Advanced Research Institute, CHA University,
4Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine,
5Department of Neurology, Johns Hopkins University School of Medicine,
6Department of Biochemistry and Molecular Biology and 7Hanyang Institute of Bioscience and Biotechnology and 8Hanyang Institute of Advanced BioConvergence, Hanyang University
Parkinson's disease (PD), characterized by dopaminergic neuron degeneration in the substantia nigra, is caused by various genetic and environmental factors. Current treatment methods are medication and surgery; however, a primary therapy has not yet been proposed. In this study, we aimed to develop a new treatment for PD that induces direct reprogramming of dopaminergic neurons (iDAN). Achaete-scute family bHLH transcription factor 1 (ASCL1) is a primary factor that initiates and regulates central nervous system development and induces neurogenesis. In addition, it interacts with BRN2 and MYT1L, which are crucial transcription factors for the direct conversion of fibroblasts into neurons. Overexpression of ASCL1 along with the transcription factors NURR1 and LMX1A can directly reprogram iDANs. Using a retrovirus, GFP-tagged ASCL1 was overexpressed in astrocytes. One week of culture in iDAN conversion medium reprogrammed the astrocytes into iDANs. After 7 days of differentiation, TH+/TUJ1+ cells emerged. After 2 weeks, the number of mature TH+/TUJ1+ dopaminergic neurons increased. Only ventral midbrain (VM) astrocytes exhibited these results, not cortical astrocytes. Thus, VM astrocytes can undergo direct iDAN reprogramming with ASCL1 alone, in the absence of transcription factors that stimulate dopaminergic neuron development.
Abstract, Accepted Manuscript [Submitted on November 22, 2023, Accepted on January 23, 2024]
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