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

iScience

Kohsuke Takeda¹  Tsuyoshi Miyakawa²  Yosuke Matsushita³  Hiroshi Kawasaki⁴  Keizo Takao⁵  Hidenori Ichijo⁶  Kazutaka Shiomi⁷  Juro Sakai⁷  Akira Futatsugi⁸  Yohei Shinmyo⁸  Masamitsu Nakazato⁹  Katsuhiko Mikoshiba^1,10  Hidde L. Ploegh^1,10  Toyomasa Katagiri^1,11  Naoya Murao^1,12  Hisae Kadowaki^1,12  Takashi Sugiyama^1,12  Hideki Nishitoh^1,13 

[1] Division of Molecular Physiology and Metabolism, Tohoku University Graduate School of Medicine, Sendai 980-8574, 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;Department of Basic Medical Sciences, Kobe City College of Nursing, 3-4 Gakuen-nishi-machi, Nishi-ku, Kobe 651-2103, Japan;Department of Behavioral Physiology, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan;Department of Cell Regulation, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan;Department of Medical Neuroscience, Graduate School of Medical Sciences, Kanazawa University, Kanazawa 920-8640, Japan;Division of Genome Medicine, Institute for Genome Research, Tokushima University, Tokushima 770-8503, Japan;Division of Metabolic Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo 153-8904, Japan;Division of Neurology, Respirology, Endocrinology, and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan;Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan;Laboratory of Biochemistry and Molecular Biology, Department of Medical Sciences, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan;RIKEN Center for Life Science Technologies (CLST), Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan;

关键词: Biological sciences;    Neuroscience;    Molecular neuroscience;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown