Suga Kei, Saito Ayako, Mishima Tatsuya, Akagawa Kimio
Department of Cell Physiology, Kyorin University School of Medicine, Mitaka, Tokyo 181-8611, Japan.
Department of Cell Physiology, Kyorin University School of Medicine, Mitaka, Tokyo 181-8611, Japan.
Neurosci Lett. 2015 Sep 14;604:30-5. doi: 10.1016/j.neulet.2015.07.017. Epub 2015 Jul 26.
Unresolved endoplasmic reticulum (ER) stress causes neuronal death and has been implicated in neurodegenerative conditions such as Alzheimer's disease (AD). However, the mechanisms by which stress signals propagate from the ER through the Golgi apparatus and their effects on the transport and processing of AD-related proteins, such as β-amyloid precursor protein (βAPP), are unknown. We recently found that in the NG108-15 cell line, ER stress upregulates ER-Golgi-soluble N-ethylmaleimide-sensitive factor-attachment protein receptors (ER-Golgi SNAREs) Syx5 and Bet1. In the present study, we examined the effects of apoptosis and ER stress inducers on the expression of ER-Golgi SNARE proteins and cell viability in a primary culture of rat hippocampal neurons. An apoptosis inducer significantly downregulated the expression of ER-Golgi SNARE Syx5. ER-stress inducers upregulated the expression of Syx5 isoforms and Bet1 proteins via de novo synthesis of their mRNA transcripts. Knockdown of Syx5 during apoptosis or ER stress induction enhanced vulnerability of neurons. Additionally, we examined the effects of Golgi stress on Syx5 expression and βAPP processing. Golgi stress also induced upregulation of ER-Golgi SNARE Syx5, and concomitantly, suppressed amyloid-β peptide secretion. These findings suggest that Syx5 is a potential stress responsive factor that participates in βAPP processing and the survival pathways of neuronal cells.
未解决的内质网（ER）应激会导致神经元死亡，并与阿尔茨海默病（AD）等神经退行性疾病有关。然而，应激信号从内质网通过高尔基体传播的机制以及它们对AD相关蛋白（如β-淀粉样前体蛋白（βAPP））的运输和加工的影响尚不清楚。我们最近发现，在NG108-15细胞系中，内质网应激会上调内质网-高尔基体可溶性N-乙基马来酰亚胺敏感因子附着蛋白受体（内质网-高尔基体SNAREs）Syx5和Bet1。在本研究中，我们检测了凋亡和内质网应激诱导剂对大鼠海马神经元原代培养物中内质网-高尔基体SNARE蛋白表达和细胞活力的影响。一种凋亡诱导剂显著下调了内质网-高尔基体SNARE Syx5的表达。内质网应激诱导剂通过其mRNA转录本的从头合成上调了Syx5亚型和Bet1蛋白的表达。在凋亡或内质网应激诱导过程中敲低Syx5会增强神经元的脆弱性。此外，我们检测了高尔基体应激对Syx5表达和βAPP加工的影响。高尔基体应激也诱导了内质网-高尔基体SNARE Syx5的上调，并同时抑制了淀粉样β肽的分泌。这些发现表明，Syx5是一种潜在的应激反应因子，参与βAPP加工和神经元细胞的存活途径。
