Regulation of Abeta secretion and protective mechanisms by Golgi stress responsive factor Syx5 and chemical compound in neuronal cells

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K06468
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 46010:Neuroscience-general-related
• Research Institution: Kyorin University
• Principal Investigator: Suga Kei 杏林大学, 医学部, 講師 (30306675)
• Co-Investigator(Kenkyū-buntansha): 山本 幸子 杏林大学, 医学部, 講師 (70434719) ; 丑丸 真 杏林大学, 医学部, 教授 (40265765)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 神経変性疾患 / アルツハイマー病 / Aベータペプチド / ゴルジストレス / SNARE / Syx5 / 神経細胞保護

Outline of Final Research Achievements

In this study, we have demonstrated that Syntaxin 5 (Syx5), an ER-Golgi SNARE is a novel Golgi-stress responsive factor. Golgi stress induced upregulation of de novo synthesis of Syx5 protein. Transcriptional induction of Syx5 mRNA was regulated by the GASE (Golgi Apparatus Stress Element) sequence present in the 5 prime region of Stx5 gene in human cells. Long exposure of neuron-glia hybrid cell line NG108-15 cells with Golgi stress inducers Monensin and GCA resulted in activation of Caspase3. Chemical chaperone PBA was used to examine the protective properties against Caspase3 activation and the production of Ab42 peptides in NG108-15 cells. Various Golgi stress inducers suppressed the secretion of Ab peptides. Total amount of secreted and intracellular Ab peptides were decreased and the ratio of Ab42 /Ab40 was increased. PBA had the ability to inhibit the Ab42 secretion and the Caspase3-dependent apoptosis in neuronal cells.

Free Research Field

神経科学

Academic Significance and Societal Importance of the Research Achievements

アルツハイマー病態の脳において見受けられるAベータ４２比の上昇は、神経細胞におけるゴルジストレス誘発の結果を反映している可能性もあると考えた。一方、他のグループから報告されているようなPBAの神経細胞保護効果は、家族性ADに連関する変異を持たない野生型ベータAPPプロセシング経路においては限定的なものであることが示唆された。