中国神经再生研究(英文版) ›› 2015, Vol. 10 ›› Issue (9): 1397-1398.doi: 10.4103/1673-5374.165227

• 观点:退行性病与再生 • 上一篇    下一篇

从适应到死亡的内质网应激与环境变化:可作为选择性神经退行性疾病干预的新靶标?

  

  • 收稿日期:2015-06-05 出版日期:2015-09-28 发布日期:2015-09-28

From adaption to death: endoplasmic reticulum stress as a novel target of selective neurodegeneration?

Yiting Liu, James R. Connor   

  1. Department of Neurology, University of Colorado at Denver, Anschutz Medical Campus, 12700 E 19thAvenue, Aurora, CO, USA (Liu Y)
    Department of Neurosurgery, Pennsylvania State University, M.S. Hershey Medical Center, 500 University Drive, Hershey, PA, USA (Connor JR)
  • Received:2015-06-05 Online:2015-09-28 Published:2015-09-28
  • Contact: Yiting Liu, Ph.D., yiting.liu@ucdenver.edu.
  • Supported by:

    This study was supported by the Paul and Harriett Campbell Fund for ALS Research, the Zimmerman Family Love Fund, and the Judith & Jean Pape Adams Charitable Foundation.

摘要:

从适应到死亡的内质网应激与环境变化:可作为选择性神经退行性疾病干预的新靶标?
神经退行性疾病是一种脑和脊髓神经元细胞亚群选择性丢失的病理条件,其中许多神经退行性疾病,如帕金森病,阿尔茨海默病,肌萎缩性侧索硬化症,多发性硬化和朊病毒病,它们的一种常见事件是含有异常聚集蛋白质体聚集造成的内质网应激水平上升。然而,神经元退变过程中引发内质网应激的确切原因尚不清楚。
内质网的正常运作在细胞生理学的许多方面都是至关重要的。据此,响应内质网功能扰动的能力被称为内质网应激,是所有细胞从根本上重要的财产。内质网应激包括折叠,错误折叠或过多蛋白质积累,钙贮存改变,内质网脂质或糖脂不平衡,氧化还原或内质网腔离子条件变化等。通过激活细胞内信号转导途径对内质网响应应激,统称为未折叠蛋白应答,在其协作下,激活下游靶基因来控制细胞以响应内质网应激,可促进两种细胞生存和促凋亡途径。 内质网应激可以是急性或慢性的,其中,慢性内质网应激可以持续耐受数天甚至数年,如在神经退行性疾病天剑下,这样一来,即使一些细胞死亡但大部分细胞将最终生存下来并具有和适应应力。显然,更好的理解和调控内质网应激水平可能对治疗神经退行性疾病十分有益。有限的神经细胞内质网应激是可以耐受的,但定位细胞仍容易受到生理性损伤。

Abstract:

Neurodegenerative disease is a condition in which subpopulations of neuronal cells of the brain and spinal cord are selectively lost. A common event in many neurodegenerative diseases, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis and prion diseases, is the increased level of endoplasmic reticulum (ER) stress caused by accumulation and deposits of inclusion bodies that contain abnormal aggregated proteins. However, the exact contributions to and causal effects of ER stress in neuron degeneration are not clear.
The proper functioning of ER is critical for numerous aspects of cell physiology. Accordingly, the ability to respond to perturbations in ER function, called ER stress, is a fundamentally important property of all cells. ER stress includes the accumulation of unfolded, misfolded or excessive protein, alterations in calcium storage, ER lipid or glycolipid imbalances, or changes in the redox or ionic conditions of the ER lumen. The ER responds to the stressors by activating intracellular signal transduction pathways, collectively called the unfolded protein response (UPR). ER stress can be acute or chronic, chronic ER stress can be persistently tolerated for days to years, as in the case of neurodegenerative diseases, so that, even if some cell death occurs, the majority of cells will ultimately survive and adapt to the stress. Clearly, a better understanding and manipulation of the ER stress level could be beneficial in treating neurodegenerative diseases. In neurons limited ER stress could be tolerated, but still position the cells to be vulnerable to a physiological insult that is sub-lethal.