TOP ＞ 共同企画

共同企画 教育講演 神経系における小胞体ストレス 7月8日（土）　13:50-15:50　Room A 3EL①-1 A Motor Neuron Disease-causing Mutation Produces Non-glycosylated Seipin that Induces ER Stress by Inactivating SERCA2b 森　和俊 京都大学 Kazutoshi Mori Kyoto University A causal relationship between endoplasmic reticulum (ER) stress and the development of neurodegenerative diseases remains controversial. Here, we focused on Seipinopathy, a dominant motor neuron disease, based on the finding that its causal gene product, Seipin, is a protein which spans the ER membrane twice. Gain-of-function mutations of Seipin produce non-glycosylated Seipin (ngSeipin), which was previously shown to induce ER stress and apoptosis at both cell and mouse levels albeit with no clarified mechanism. We found that aggregation-prone ngSeipin dominantly inactivated SERCA2b, the major calcium pump in the ER, and decreased the calcium concentration in the ER, leading to ER stress and apoptosis in human colorectal carcinoma-derived cells (HCT116). This inactivation required oligomerization of ngSeipin and direct interaction of the C-terminus of ngSeipin with SERCA2b, and was observed in Seipin-deficient neuroblastoma (SH-SY5Y) cells expressing ngSeipin at an endogenous protein level. Our results thus provide a new direction to the controversy noted above. 7月8日（土）　13:50-15:50　Room A 3EL①-2 脳虚血における小胞体ストレス Endoplasmic reticulum (ER) stress in the brain ischemia 堀　修 金沢大学　医学系　神経解剖学 Osamu Hori Dept of Neuroanatomy, Kanazawa University, Kanazawa, Japan Endoplasmic reticulum (ER) stress is characterized by the accumulation of unfolded proteins in the ER, and occurs in many pathophysiological conditions including ischemia/energy starvation, disturbance of Ca2+ homeostasis and production of a large amount of proteins in the ER. We and other groups have reported that brain ischemia causes ER stress and activates the unfolded protein response (UPR), a cellular stress response against ER stress, which is composed of, at least, three different branches, such as Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (Ire1), and activating transcription factor 6 (ATF6). Among these, ATF6 branch transmits ER stress and induces molecular chaperones and folding enzymes in the ER. We have reported important roles of ATF6 branch and downstream-molecular chaperons for both of neuronal survival and astroglial activation after brain ischemia. Furthermore, we recently found that brain ischemia activated the UPR in cell-type-specific and time-dependent manner. In this symposium, I would like to summarize the role of the UPR in both neuronal and non-neuronal cells after brain ischemia, and discuss possibilities as a therapeutic target for stroke and other acute brain injury. 7月8日（土）　13:50-15:50　Room A 3EL①-3 小胞体品質管理システムとその破綻による脳神経疾患 Endoplasmic reticulum quality control system and neurodegenerative diseases resulting from its disruption 西頭　英起 宮崎大学　医学部　機能生化学 Hideki Nishitoh Lab. of Biochem. and Mol. Biol., Faculty of Med., Univ. of Miyazaki The pathogenic molecular mechanisms of neurodegenerative diseases involve the dysfunction of various organelles. The endoplasmic reticulum (ER) plays an important role in the formation and maintenance of neurite and synaptic function, and ER quality control dysfunction is closely related to various neurodegenerative diseases. Accumulation of abnormal proteins observed in neurodegenerative diseases and aging brains leads to a decrease in proteasome activity, which imposes a load on the protein degradation system related to the ER, resulting in ER stress. However, the mechanisms by which ER stress leads to neuronal dysfunction are still poorly understood. Chemical chaperones that suppress the accumulation of abnormal proteins improve ER quality and restore brain function in model animals of SCA and ALS, and clinical trials are underway in several countries. However, the detailed mechanisms by which chemical chaperones restore brain function are still unclear. In this lecture, I will provide an overview of ER quality control systems, particularly protein degradation systems in the vicinity of the ER membrane, and report on the morphological and functional impairment of the central nervous system due to ER stress, as well as the recovery of brain function by compounds, presenting a proof of concept for new therapies for neurodegenerative diseases in the future.