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Home › News and Events › 2022 › Researches › ALS-related protein TDP-43 regulates cholesterol synthesis ~Insight for molecular mechanisms of lipid metabolism and nutritional therapy in ALS~

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May 20, 2022

ALS-related protein TDP-43 regulates cholesterol synthesis ~Insight for molecular mechanisms of lipid metabolism and nutritional therapy in ALS~

The Haruhisa Inoue lab finds the molecular mechanisms underlying the decrease in cholesterol levels in ALS. Increased TDP-43, an ALS pathogenic protein, decreases the activity of SREBP2, a transcription factor that regulates cholesterol synthesis.

In a previous study using iPS cells from patients with TAR DNA-binding protein of 43 kDa (TDP-43) mutations, the research group found that the expression of genes related to lipid metabolism was reduced in the motor neurons of amyotrophic lateral sclerosis (ALS) patients (CiRA News: August 1, 2012). In addition, clinical evidence has demonstrated that nutritional therapy with a high-calorie, high-lipid diet improves the life expectancy of ALS. However, the molecular mechanisms have not been explored. To address this clinical question, the research group conducted a new study to pursue reverse translational research focusing on TDP-43, the major pathogenic protein of ALS.

Using cell lines overexpressing TDP-43, ALS model mice, and cerebrospinal fluid samples from ALS patients, the researchers found that elevated TDP-43 decreases the activity of SREBP2, a transcription factor that regulates cholesterol synthesis. This reverse translational research revealed one of the molecular mechanisms of lipid metabolism abnormalities and the efficacy of nutritional therapy in ALS.

The results of this study were published online in Scientific Reports on May 14, 2022.

Paper Details
  • Journal: Scientific Reports
  • Title: TDP-43 regulates cholesterol biosynthesis by inhibiting sterol regulatory element-binding protein 2
  • Authors: Naohiro Egawa1,2,3, Yuishin Izumi4, Hidefumi Suzuki1,2,3, Itaru Tsuge1,5, Koji Fujita4, Hitoshi Shimano6, Keiichi Izumikawa7, Nobuhiro Takahashi7, Kayoko Tsukita1,3, Takako Enami1,8, Masahiro Nakamura1, Akira Watanabe1,9, Motoko Naitoh5, Shigehiko Suzuki5, Tsuneyoshi Seki10, Kazuhiro Kobayashi10, Tatsushi Toda10,11, Ryuji Kaji4, Ryosuke Takahashi2, Haruhisa Inoue1,3,8*
  • Author Affiliations:
    1. Center for iPS Cell Research and Application (CiRA), Kyoto University
    2. Department of Neurology, Graduate School of Medicine, Kyoto University
    3. iPSC Based Drug Discovery and Development Team, RIKEN BioResource Research Center (BRC)
    4. Department of Clinical Neuroscience, The University of Tokushima Graduate School
    5. Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, Kyoto University
    6. Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukub
    7. Department of Applied Biological Science, Graduate School of Agriculture, Tokyo University of Agriculture and Technology
    8. Medical Risk Avoidance Based On iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP)
    9. Medical Innovation Center, Graduate School of Medicine, Kyoto University
    10. Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine
    11. Department of Neurology, Graduate School of Medicine, The University of Tokyo
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