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TDP-43 regulates cholesterol biosynthesis by inhibiting sterol regulatory element-binding protein 2

Egawa, Naohiro Izumi, Yuishin Suzuki, Hidefumi Tsuge, Itaru Fujita, Koji Shimano, Hitoshi Izumikawa, Keiichi Takahashi, Nobuhiro Tsukita, Kayoko Enami, Takako Nakamura, Masahiro Watanabe, Akira Naitoh, Motoko Suzuki, Shigehiko Seki, Tsuneyoshi Kobayashi, Kazuhiro Toda, Tatsushi Kaji, Ryuji Takahashi, Ryosuke Inoue, Haruhisa 京都大学 DOI:10.1038/s41598-022-12133-4

2022

概要

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.

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Acknowledgements

We would like to express our sincere gratitude to all our coworkers and collaborators, to Dr. Marta Valenza, Dr.

Elena Cattaneo, Dr. Yoshihiro Yoneda for providing plasmids, and to Dr. Keiko Imamura for supportive experiments and iPS Cell Research Fund.

Author contributions

H.I. conceived and planned the project. N.E., H.Shi., and H.I. designed the experiments. N.E. and H.I. wrote

the manuscript. N.E., H.Su., I.T., K.T., T.E., M.Nak., A.W., M. Nai., S.S., T.S., K.K. and T.T. performed the

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experiments. R.T. did critical reading. Y.I., K.F. and R.K. recruited patients and analyzed their spinal fluids. K.I.

and N.T. generated DAP-TDP-43 cell lines. All authors reviewed the manuscript.

Funding

This research was funded in part by a Grant for the Core Center for iPS Cell Research of the Research Center

Network for Realization of Regenerative Medicine from AMED to H.I. and the Nakabayashi Trust for ALS

Research (N.E.).

Competing interests The authors declare no competing interests.

Additional information

Supplementary Information The online version contains supplementary material available at https://doi.org/

10.1038/s41598-022-12133-4.

Correspondence and requests for materials should be addressed to H.I.

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TDP-43 regulates cholesterol biosynthesis by inhibiting sterol regulatory element-binding protein 2

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関連論文

Conformational change of RNA‐helicase DHX30 by ALS/FTD‐linked FUS induces mitochondrial dysfunction and cytosolic aggregates

Ndufs4 ablation shows an elevated GFAP and a decreased synaptophysin expression in mouse hippocampus.

Study on the role of CtBP2 in pancreatic β cell

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