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

doi:10.1016/j.isci.2021.102758

ERAD components Derlin-1 and Derlin-2 are essential for postnatal brain development and motor function

iScience. 2021 Jun 19;24(7):102758. doi: 10.1016/j.isci.2021.102758. eCollection 2021 Jul 23.

Authors

Takashi Sugiyama¹, Naoya Murao¹, Hisae Kadowaki¹, Keizo Takao^{2

3

4}, Tsuyoshi Miyakawa⁵, Yosuke Matsushita⁶, Toyomasa Katagiri⁶, Akira Futatsugi⁷, Yohei Shinmyo⁸, Hiroshi Kawasaki⁸, Juro Sakai^{9

10}, Kazutaka Shiomi¹¹, Masamitsu Nakazato¹¹, Kohsuke Takeda¹², Katsuhiko Mikoshiba^{13

14

15}, Hidde L Ploegh¹⁶, Hidenori Ichijo¹⁷, Hideki Nishitoh^{1

18}

Affiliations

¹ Laboratory of Biochemistry and Molecular Biology, Department of Medical Sciences, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.
² Department of Behavioral Physiology, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan.
³ Research Center for Idling Brain Science, University of Toyama, Toyama, Japan.
⁴ Section of Behavioral Patterns, Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, Japan.
⁵ Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan.
⁶ Division of Genome Medicine, Institute for Genome Research, Tokushima University, Tokushima 770-8503, Japan.
⁷ Department of Basic Medical Sciences, Kobe City College of Nursing, 3-4 Gakuen-nishi-machi, Nishi-ku, Kobe 651-2103, Japan.
⁸ Department of Medical Neuroscience, Graduate School of Medical Sciences, Kanazawa University, Kanazawa 920-8640, Japan.
⁹ Division of Metabolic Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo 153-8904, Japan.
¹⁰ Division of Molecular Physiology and Metabolism, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.
¹¹ Division of Neurology, Respirology, Endocrinology, and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.
¹² Department of Cell Regulation, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
¹³ RIKEN Center for Life Science Technologies (CLST), Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan.
¹⁴ Shanghai Institute for Advanced Immunochemical Studies (SIAIS), Shanghai Tech University, Shanghai, China.
¹⁵ Department of Biomolecular Science, Faculty of Science, Toho University, Funabashi, Japan.
¹⁶ Boston Children's Hospital and Harvard Medical School, 1 Blackfan Circle, Boston, MA 02115, USA.
¹⁷ Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
¹⁸ Frontier Science Research Center, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.

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.