Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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A comparison study of pathological features and drug efficacy between Drosophila models of C9orf72 ALS/FTD

  • Davin Lee (Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST)) ;
  • Hae Chan Jeong (Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST)) ;
  • Seung Yeol Kim (SK Biopharmaceuticals Co., Ltd.) ;
  • Jin Yong Chung (SK Biopharmaceuticals Co., Ltd.) ;
  • Seok Hwan Cho (SK Biopharmaceuticals Co., Ltd.) ;
  • Kyoung Ah Kim (Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST)) ;
  • Jae Ho Cho (Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST)) ;
  • Byung Su Ko (Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST)) ;
  • In Jun Cha (Brain Research Policy Center, Korea Brain Research Institute) ;
  • Chang Geon Chung (Department of Neurology, Johns Hopkins University School of Medicine) ;
  • Eun Seon Kim (Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST)) ;
  • Sung Bae Lee (Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST))
  • Received : 2023.07.28
  • Accepted : 2023.11.13
  • Published : 2024.01.31
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Abstract

Amyotrophic lateral sclerosis is a devastating neurodegenerative disease with a complex genetic basis, presenting both in familial and sporadic forms. The hexanucleotide (G4C2) repeat expansion in the C9orf72 gene, which triggers distinct pathogenic mechanisms, has been identified as a major contributor to familial and sporadic Amyotrophic lateral sclerosis cases. Animal models have proven pivotal in understanding these mechanisms; however, discrepancies between models due to variable transgene sequence, expression levels, and toxicity profiles complicate the translation of findings. Herein, we provide a systematic comparison of 7 publicly available Drosophila transgenes modeling the G4C2 expansion under uniform conditions, evaluating variations in their toxicity profiles. Further, we tested 3 previously characterized disease-modifying drugs in selected lines to uncover discrepancies among the tested strains. Our study not only deepens our understanding of the C9orf72 G4C2 mutations but also presents a framework for comparing constructs with minute structural differences. This work may be used to inform experimental designs to better model disease mechanisms and help guide the development of targeted interventions for neurodegenerative diseases, thus bridging the gap between model-based research and therapeutic application.

Keywords

Acknowledgement

This work was supported by Basic Science Research Program through the National Research Foundation of Korea (2022R1A4A2000703 and 2021R1A2C1003817) and the Korea Brain Research Institute Research Program (23-BR-03-02), funded by the Ministry of Science and ICT, Republic of Korea and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute and Korea Dementia Research Center (KDRC), funded by the Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea (HU21C0027)

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