TDP-43 regulates cholesterol biosynthesis by inhibiting sterol regulatory element-binding protein 2
Abstract Dyslipidemia is considered an essential component of the pathological process of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disease. Although TAR DNA Binding Protein 43 kDa (TDP-43) links both familial and sporadic forms of ALS and cytoplasmic aggregates are a hallmark of mos...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-05-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-12133-4 |
| _version_ | 1818008196269211648 |
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| author | Naohiro Egawa Yuishin Izumi Hidefumi Suzuki Itaru Tsuge Koji Fujita Hitoshi Shimano Keiichi Izumikawa Nobuhiro Takahashi Kayoko Tsukita Takako Enami Masahiro Nakamura Akira Watanabe Motoko Naitoh Shigehiko Suzuki Tsuneyoshi Seki Kazuhiro Kobayashi Tatsushi Toda Ryuji Kaji Ryosuke Takahashi Haruhisa Inoue |
| author_facet | Naohiro Egawa Yuishin Izumi Hidefumi Suzuki Itaru Tsuge Koji Fujita Hitoshi Shimano Keiichi Izumikawa Nobuhiro Takahashi Kayoko Tsukita Takako Enami Masahiro Nakamura Akira Watanabe Motoko Naitoh Shigehiko Suzuki Tsuneyoshi Seki Kazuhiro Kobayashi Tatsushi Toda Ryuji Kaji Ryosuke Takahashi Haruhisa Inoue |
| author_sort | Naohiro Egawa |
| collection | DOAJ |
| description | Abstract Dyslipidemia is considered an essential component of the pathological process of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disease. Although TAR DNA Binding Protein 43 kDa (TDP-43) links both familial and sporadic forms of ALS and cytoplasmic aggregates are a hallmark of most cases of ALS, the molecular mechanism and the in vivo relation of ALS dyslipidemia with TDP-43 have been unclear. To analyze the dyslipidemia-related gene expression by TDP-43, we performed expression microarray and RNA deep sequencing (RNA-Seq) using cell lines expressing high levels of TDP-43 and identified 434 significantly altered genes including sterol regulatory element-binding protein 2 (SREBP2), a master regulator of cholesterol homeostasis and its downstream genes. Elevated TDP-43 impaired SREBP2 transcriptional activity, leading to inhibition of cholesterol biosynthesis. The amount of cholesterol was significantly decreased in the spinal cords of TDP-43-overexpressed ALS model mice and in the cerebrospinal fluids of ALS patients. These results suggested that TDP-43 could play an essential role in cholesterol biosynthesis in relation to ALS dyslipidemia. |
| first_indexed | 2024-04-14T05:26:05Z |
| format | Article |
| id | doaj.art-28b5a033d5004d9786adf1561756bcbc |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-14T05:26:05Z |
| publishDate | 2022-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-28b5a033d5004d9786adf1561756bcbc2022-12-22T02:09:57ZengNature PortfolioScientific Reports2045-23222022-05-0112111210.1038/s41598-022-12133-4TDP-43 regulates cholesterol biosynthesis by inhibiting sterol regulatory element-binding protein 2Naohiro Egawa0Yuishin Izumi1Hidefumi Suzuki2Itaru Tsuge3Koji Fujita4Hitoshi Shimano5Keiichi Izumikawa6Nobuhiro Takahashi7Kayoko Tsukita8Takako Enami9Masahiro Nakamura10Akira Watanabe11Motoko Naitoh12Shigehiko Suzuki13Tsuneyoshi Seki14Kazuhiro Kobayashi15Tatsushi Toda16Ryuji Kaji17Ryosuke Takahashi18Haruhisa Inoue19Center for iPS Cell Research and Application (CiRA), Kyoto UniversityDepartment of Clinical Neuroscience, The University of Tokushima Graduate SchoolCenter for iPS Cell Research and Application (CiRA), Kyoto UniversityCenter for iPS Cell Research and Application (CiRA), Kyoto UniversityDepartment of Clinical Neuroscience, The University of Tokushima Graduate SchoolDepartment of Endocrinology and Metabolism, Faculty of Medicine, University of TsukubaDepartment of Applied Biological Science, Graduate School of Agriculture, Tokyo University of Agriculture and TechnologyDepartment of Applied Biological Science, Graduate School of Agriculture, Tokyo University of Agriculture and TechnologyCenter for iPS Cell Research and Application (CiRA), Kyoto UniversityCenter for iPS Cell Research and Application (CiRA), Kyoto UniversityCenter for iPS Cell Research and Application (CiRA), Kyoto UniversityCenter for iPS Cell Research and Application (CiRA), Kyoto UniversityDepartment of Plastic and Reconstructive Surgery, Graduate School of Medicine, Kyoto UniversityDepartment of Plastic and Reconstructive Surgery, Graduate School of Medicine, Kyoto UniversityDivision of Neurology/Molecular Brain Science, Kobe University Graduate School of MedicineDivision of Neurology/Molecular Brain Science, Kobe University Graduate School of MedicineDivision of Neurology/Molecular Brain Science, Kobe University Graduate School of MedicineDepartment of Clinical Neuroscience, The University of Tokushima Graduate SchoolDepartment of Neurology, Graduate School of Medicine, Kyoto UniversityCenter for iPS Cell Research and Application (CiRA), Kyoto UniversityAbstract Dyslipidemia is considered an essential component of the pathological process of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disease. Although TAR DNA Binding Protein 43 kDa (TDP-43) links both familial and sporadic forms of ALS and cytoplasmic aggregates are a hallmark of most cases of ALS, the molecular mechanism and the in vivo relation of ALS dyslipidemia with TDP-43 have been unclear. To analyze the dyslipidemia-related gene expression by TDP-43, we performed expression microarray and RNA deep sequencing (RNA-Seq) using cell lines expressing high levels of TDP-43 and identified 434 significantly altered genes including sterol regulatory element-binding protein 2 (SREBP2), a master regulator of cholesterol homeostasis and its downstream genes. Elevated TDP-43 impaired SREBP2 transcriptional activity, leading to inhibition of cholesterol biosynthesis. The amount of cholesterol was significantly decreased in the spinal cords of TDP-43-overexpressed ALS model mice and in the cerebrospinal fluids of ALS patients. These results suggested that TDP-43 could play an essential role in cholesterol biosynthesis in relation to ALS dyslipidemia.https://doi.org/10.1038/s41598-022-12133-4 |
| spellingShingle | Naohiro Egawa Yuishin Izumi Hidefumi Suzuki Itaru Tsuge Koji Fujita Hitoshi Shimano Keiichi Izumikawa Nobuhiro Takahashi Kayoko Tsukita Takako Enami Masahiro Nakamura Akira Watanabe Motoko Naitoh Shigehiko Suzuki Tsuneyoshi Seki Kazuhiro Kobayashi Tatsushi Toda Ryuji Kaji Ryosuke Takahashi Haruhisa Inoue TDP-43 regulates cholesterol biosynthesis by inhibiting sterol regulatory element-binding protein 2 Scientific Reports |
| title | TDP-43 regulates cholesterol biosynthesis by inhibiting sterol regulatory element-binding protein 2 |
| title_full | TDP-43 regulates cholesterol biosynthesis by inhibiting sterol regulatory element-binding protein 2 |
| title_fullStr | TDP-43 regulates cholesterol biosynthesis by inhibiting sterol regulatory element-binding protein 2 |
| title_full_unstemmed | TDP-43 regulates cholesterol biosynthesis by inhibiting sterol regulatory element-binding protein 2 |
| title_short | TDP-43 regulates cholesterol biosynthesis by inhibiting sterol regulatory element-binding protein 2 |
| title_sort | tdp 43 regulates cholesterol biosynthesis by inhibiting sterol regulatory element binding protein 2 |
| url | https://doi.org/10.1038/s41598-022-12133-4 |
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