ERAD components Derlin-1 and Derlin-2 are essential for postnatal brain development and motor function
Takashi Sugiyama,
Naoya Murao,
Hisae Kadowaki,
Keizo Takao,
Tsuyoshi Miyakawa,
Yosuke Matsushita,
Toyomasa Katagiri,
Akira Futatsugi,
Yohei Shinmyo,
Hiroshi Kawasaki,
Juro Sakai,
Kazutaka Shiomi,
Masamitsu Nakazato,
Kohsuke Takeda,
Katsuhiko Mikoshiba,
Hidde L. Ploegh,
Hidenori Ichijo,
Hideki Nishitoh
Affiliations
Takashi Sugiyama
Laboratory of Biochemistry and Molecular Biology, Department of Medical Sciences, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan
Naoya Murao
Laboratory of Biochemistry and Molecular Biology, Department of Medical Sciences, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan
Hisae Kadowaki
Laboratory of Biochemistry and Molecular Biology, Department of Medical Sciences, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan
Keizo Takao
Department of Behavioral Physiology, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan; Research Center for Idling Brain Science, University of Toyama, Toyama, Japan; Section of Behavioral Patterns, Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, Japan
Tsuyoshi Miyakawa
Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan
Yosuke Matsushita
Division of Genome Medicine, Institute for Genome Research, Tokushima University, Tokushima 770-8503, Japan
Toyomasa Katagiri
Division of Genome Medicine, Institute for Genome Research, Tokushima University, Tokushima 770-8503, Japan
Akira Futatsugi
Department of Basic Medical Sciences, Kobe City College of Nursing, 3-4 Gakuen-nishi-machi, Nishi-ku, Kobe 651-2103, Japan
Yohei Shinmyo
Department of Medical Neuroscience, Graduate School of Medical Sciences, Kanazawa University, Kanazawa 920-8640, Japan
Hiroshi Kawasaki
Department of Medical Neuroscience, Graduate School of Medical Sciences, Kanazawa University, Kanazawa 920-8640, Japan
Juro Sakai
Division of Metabolic Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo 153-8904, Japan; Division of Molecular Physiology and Metabolism, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
Kazutaka Shiomi
Division of Neurology, Respirology, Endocrinology, and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan
Masamitsu Nakazato
Division of Neurology, Respirology, Endocrinology, and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan
Kohsuke Takeda
Department of Cell Regulation, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
Katsuhiko Mikoshiba
RIKEN Center for Life Science Technologies (CLST), Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan; Shanghai Institute for Advanced Immunochemical Studies (SIAIS), Shanghai Tech University, Shanghai, China; Department of Biomolecular Science, Faculty of Science, Toho University, Funabashi, Japan
Hidde L. Ploegh
Boston Children's Hospital and Harvard Medical School, 1 Blackfan Circle, Boston, MA 02115, USA
Hidenori Ichijo
Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan; Corresponding author
Hideki Nishitoh
Laboratory of Biochemistry and Molecular Biology, Department of Medical Sciences, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan; Frontier Science Research Center, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan; Corresponding author
Summary: 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.
