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...

ver descrição completa

Na minha lista:
Detalhes bibliográficos
Main Authors: 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
Formato: Artigo
Idioma:Inglês
Publicado em: Nature Portfolio 2022-05-01
Colecção:Scientific Reports
Acesso em linha:https://doi.org/10.1038/s41598-022-12133-4
Tags: Adicionar Tag
Sem tags, seja o primeiro a adicionar uma tag!
id oai:doaj.org-article:28b5a033d5004d9786adf1561756bcbc
record_format Article
spelling oai:doaj.org-article:28b5a033d5004d9786adf1561756bcbc2022-05-15T11:17:09ZengNature 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
institution DOAJ
collection Directory of Open Access Journals
language Inglês
format Artigo
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
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
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
title 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_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_sort tdp-43 regulates cholesterol biosynthesis by inhibiting sterol regulatory element-binding protein 2
publisher Nature Portfolio
series Scientific Reports
issn 2045-2322
publishDate 2022-05-01
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.
url https://doi.org/10.1038/s41598-022-12133-4
_version_ 1733796259651649536