The endoplasmic reticulum (ER) is the largest organelle of the cell, composed of a continuous network of sheets and tubules, and is involved in protein, calcium (Ca2+), and lipid homeostasis. In neurons, the ER extends throughout the cell, both somal and axodendritic compartments, and is highly important for neuronal functions. A third of the proteome of a cell, secreted and membrane-bound proteins, are processed within the ER lumen and most of these proteins are vital for neuronal activity. The brain itself is high in lipid content, and many structural lipids are produced, in part, by the ER. Cholesterol and steroid synthesis are strictly regulated in the ER of the blood-brain barrier protected brain cells. The high Ca2+ level in the ER lumen and low cytosolic concentration is needed for Ca2+-based intracellular signaling, for synaptic signaling and Ca2+ waves, and for preparing proteins for correct folding in the presence of high Ca2+ concentrations to cope with the high concentrations of extracellular milieu. Particularly, ER Ca2+ is controlled in axodendritic areas for proper neurito- and synaptogenesis and synaptic plasticity and remodeling. In this review, we cover the physiologic functions of the neuronal ER and discuss it in context of common neurodegenerative diseases, focusing on pharmacological regulation of ER Ca2+ Furthermore, we postulate that heterogeneity of the ER, its protein folding capacity, and ensuring Ca2+ regulation are crucial factors for the aging and selective vulnerability of neurons in various neurodegenerative diseases. SIGNIFICANCE STATEMENT: Endoplasmic reticulum (ER) Ca2+ regulators are promising therapeutic targets for degenerative diseases for which efficacious drug therapies do not exist. The use of pharmacological probes targeting maintenance and restoration of ER Ca2+ can provide restoration of protein homeostasis (e.g., folding of complex plasma membrane signaling receptors) and slow down the degeneration process of neurons.

中文翻译：

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内质网结构和钙动力学的药理学调节：对神经退行性疾病的重要性。

内质网 (ER) 是细胞最大的细胞器，由片层和小管的连续网络组成，参与蛋白质、钙 (Ca2+) 和脂质稳态。在神经元中，内质网延伸到整个细胞，包括体细胞和轴突细胞，对神经元功能非常重要。细胞蛋白质组的三分之一，即分泌蛋白和膜结合蛋白，在内质网腔内进行加工，其中大多数蛋白质对于神经元活动至关重要。大脑本身的脂质含量很高，许多结构脂质部分是由内质网产生的。胆固醇和类固醇的合成在受血脑屏障保护的脑细胞的内质网中受到严格调节。基于 Ca2+ 的细胞内信号传导、突触信号传导和 Ca2+ 波，以及在高 Ca2+ 浓度存在下制备正确折叠的蛋白质以应对高浓度的细胞外信号，需要内质网腔内的高 Ca2+ 水平和低胞质浓度。环境。特别是，ER Ca2+ 在轴突区域受到控制，以实现适当的神经和突触发生以及突触可塑性和重塑。在这篇综述中，我们涵盖了神经元 ER 的生理功能，并在常见的神经退行性疾病的背景下对其进行了讨论，重点关注 ER Ca2+ 的药理学调节。此外，我们假设 ER 的异质性、其蛋白质折叠能力和确保 Ca2+ 调节是各种神经退行性疾病中神经元衰老和选择性脆弱性的关键因素。意义陈述：内质网 (ER) Ca2+ 调节剂是退行性疾病的有前景的治疗靶点，而目前尚无有效的药物疗法。使用针对 ER Ca2+ 维持和恢复的药理学探针可以恢复蛋白质稳态（例如，复杂质膜信号受体的折叠）并减缓神经元的退化过程。