@article{7671611917304bbe948dfce4da073525,
title = "ERAD components Derlin-1 and Derlin-2 are essential for postnatal brain development and motor function",
abstract = "Derlin family members (Derlins) are primarily known as components of the endoplasmic reticulum-associated degradation pathway that eliminates misfolded proteins. Here we report a function of Derlins in the brain development. Deletion of Derlin-1 or Derlin-2 in the central nervous system of mice impaired postnatal brain development, particularly of the cerebellum and striatum, and induced motor control deficits. Derlin-1 or Derlin-2 deficiency reduced neurite outgrowth in vitro and in vivo and surprisingly also inhibited sterol regulatory element binding protein 2 (SREBP-2)-mediated brain cholesterol biosynthesis. In addition, reduced neurite outgrowth due to Derlin-1 deficiency was rescued by SREBP-2 pathway activation. Overall, our findings demonstrate that Derlins sustain brain cholesterol biosynthesis, which is essential for appropriate postnatal brain development and function.",
keywords = "Biological sciences, Molecular neuroscience, Neuroscience",
author = "Takashi Sugiyama and Naoya Murao and Hisae Kadowaki and Keizo Takao and Tsuyoshi Miyakawa and Yosuke Matsushita and Toyomasa Katagiri and Akira Futatsugi and Yohei Shinmyo and Hiroshi Kawasaki and Juro Sakai and Kazutaka Shiomi and Masamitsu Nakazato and Kohsuke Takeda and Katsuhiko Mikoshiba and Ploegh, {Hidde L.} and Hidenori Ichijo and Hideki Nishitoh",
note = "Funding Information: We thank Dr. R. Kageyama (Kyoto University) for Tg(Nes-Cre)1Kag mice, Dr. R. Sato (The University of Tokyo) for SREBP-2 expression plasmid, Dr. D. Trono (Ecole Polytechnique F{\'e}d{\'e}rale de Lausanne) for lentivirus packaging vector constructs, and Drs. T. Udagawa (Tohoku University), K. Kokame, and Y. Eura (National Cerebral and Cardiovascular Center) for technical assistance and discussion. This study was supported by AMED under grant number JP19gm5010001 (H.I.), MEXT/JSPS KAKENHI (grant number 18H03995 [H.I.], 17K15624 and 19K16016 [N.M.], 18K06222 [H. Kadowaki], 16H06276, 17H05670, 17H06419, and 18H02973 [H.N.]), Grant for Clinical Research from Miyazaki University Hospital (T.S.), Mitsubishi Foundation, Uehara Memorial Foundation, Astellas Foundation for Research on Metabolic Disorders, Takeda Science Foundation, and Joint Usage and Joint Research Programs, Institute of Advanced Medical Sciences, Tokushima University (H.N.). T.S. conceptualization, investigation, and writing-original draft. N.M. conceptualization, funding acquisition, investigation, and writing-original draft. H.Kadowaki conceptualization, funding acquisition, investigation, supervision, and writing-review and editing. K.Takao, T.M. and T.K. resources and methodology. Y.M. investigation and methodology. A.F. Y.S. H.Kawasaki, K.Takeda, K.M. and H.L.P. resources. J.S. methodology. K.S. and M.N. supervision. H.I. resources, funding acquisition, and supervision. H.N. conceptualization, data curation, supervision, funding acquisition, project administration and writing-original draft, review, and editing. The authors declare no competing interests. We worked to ensure diversity in experimental samples through the selection of the cell lines. We worked to ensure diversity in experimental samples through the selection of the genomic datasets. The author list of this paper includes contributors from the location where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. Funding Information: We thank Dr. R. Kageyama (Kyoto University) for Tg(Nes-Cre)1Kag mice, Dr. R. Sato (The University of Tokyo) for SREBP-2 expression plasmid, Dr. D. Trono (Ecole Polytechnique F{\'e}d{\'e}rale de Lausanne) for lentivirus packaging vector constructs, and Drs. T. Udagawa (Tohoku University), K. Kokame, and Y. Eura (National Cerebral and Cardiovascular Center) for technical assistance and discussion. This study was supported by AMED under grant number JP19gm5010001 (H.I.), MEXT /JSPS KAKENHI (grant number 18H03995 [H.I.], 17K15624 and 19K16016 [N.M.], 18K06222 [H. Kadowaki], 16H06276 , 17H05670 , 17H06419 , and 18H02973 [H.N.]), Grant for Clinical Research from Miyazaki University Hospital (T.S.), Mitsubishi Foundation, Uehara Memorial Foundation, Astellas Foundation for Research on Metabolic Disorders, Takeda Science Foundation, and Joint Usage and Joint Research Programs, Institute of Advanced Medical Sciences, Tokushima University (H.N.). Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = jul,
day = "23",
doi = "10.1016/j.isci.2021.102758",
language = "English",
volume = "24",
journal = "iScience",
issn = "2589-0042",
publisher = "Elsevier Inc.",
number = "7",
}