Sugiyama Takashi, Murao Naoya, Kadowaki Hisae, Takao Keizo, Miyakawa Tsuyoshi, Matsushita Yosuke, Katagiri Toyomasa, Futatsugi Akira, Shinmyo Yohei, Kawasaki Hiroshi, Sakai Juro, Shiomi Kazutaka, Nakazato Masamitsu, Takeda Kohsuke, Mikoshiba Katsuhiko, Ploegh Hidde L, Ichijo Hidenori, Nishitoh Hideki
Laboratory of Biochemistry and Molecular Biology, Department of Medical Sciences, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.
Department of Behavioral Physiology, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan.
iScience. 2021 Jun 19;24(7):102758. doi: 10.1016/j.isci.2021.102758. eCollection 2021 Jul 23.
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 or 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 and 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.
Derlin家族成员（Derlins）主要作为内质网相关降解途径的组成部分而为人所知，该途径可清除错误折叠的蛋白质。在此，我们报告了Derlins在大脑发育中的功能。在小鼠中枢神经系统中缺失Derlin-1或Derlin-2会损害出生后大脑的发育，尤其是小脑和纹状体，并导致运动控制缺陷。Derlin-1或Derlin-2缺陷会减少神经突生长，并且令人惊讶的是，还会抑制固醇调节元件结合蛋白2（SREBP-2）介导的脑胆固醇生物合成。此外，SREBP-2途径激活可挽救因Derlin-1缺陷而导致的神经突生长减少。总体而言，我们的研究结果表明，Derlins维持脑胆固醇生物合成，这对出生后大脑的正常发育和功能至关重要。
