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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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ASCL1-mediated direct reprogramming: converting ventral midbrain astrocytes into dopaminergic neurons for Parkinson's disease therapy

  • Sang Hui Yong (Graduate School of Biomedical Science and Engineering, Hanyang University) ;
  • Sang-Mi Kim (Hanyang Biomedical Research Institute, Hanyang University) ;
  • Gyeong Woon Kong (Graduate School of Biomedical Science and Engineering, Hanyang University) ;
  • Seung Hwan Ko (Graduate School of Biomedical Science and Engineering, Hanyang University) ;
  • Eun-Hye Lee (Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine) ;
  • Yohan Oh (Graduate School of Biomedical Science and Engineering, Hanyang University) ;
  • Chang-Hwan Park (Graduate School of Biomedical Science and Engineering, Hanyang University)
  • Received : 2023.11.22
  • Accepted : 2024.01.23
  • Published : 2024.08.31
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Abstract

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 convertsion 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 neurons development.

Keywords

Acknowledgement

This research was supported by grants from the Basic Science Research Program (NRF-2019R1A2C2005681), the K-Brain Project of the National Research Foundation funded by Ministry of Science and ICT (RS-2023-00266171), and the Korea Dementia Research Project through the Korea Dementia Research Center funded by Ministry of Health and Welfare and MSIT (HU22C0143).

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