Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, South Carolina. United States.
Curr Pharm Des. 2017;23(33):5010-5021. doi: 10.2174/1381612823666170622095802.
Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of motor neurons in the spinal cord, brain stem, and motor cortex. The molecular mechanism underlying the progressive degeneration of motor neuron remains uncertain but involves a non-cell autonomous process. In acute injury or degenerative diseases astrocytes adopt a reactive phenotype known as astrogliosis. Astrogliosis is a complex remodeling of astrocyte biology and most likely represents a continuum of potential phenotypes that affect neuronal function and survival in an injury-specific manner. In ALS patients, reactive astrocytes surround both upper and lower degenerating motor neurons and play a key role in the pathology. It has become clear that astrocytes play a major role in ALS pathology. Through loss of normal function or acquired new characteristics, astrocytes are able to influence motor neuron fate and the progression of the disease. The use of different cell culture models indicates that ALS-astrocytes are able to induce motor neuron death by secreting a soluble factor(s). Here, we discuss several pathogenic mechanisms that have been proposed to explain astrocyte-mediated motor neuron death in ALS. In addition, examples of strategies that revert astrocyte-mediated motor neuron toxicity are reviewed to illustrate the therapeutic potential of astrocytes in ALS. Due to the central role played by astrocytes in ALS pathology, therapies aimed at modulating astrocyte biology may contribute to the development of integral therapeutic approaches to halt ALS progression.
肌萎缩侧索硬化症（ALS）的特征是脊髓、脑干和运动皮层中的运动神经元进行性退化。运动神经元进行性退化的分子机制尚不清楚，但涉及非细胞自主过程。在急性损伤或退行性疾病中，星形胶质细胞表现出一种称为星形胶质细胞增生的反应性表型。星形胶质细胞增生是星形胶质细胞生物学的复杂重塑，很可能代表了一种以损伤特异性方式影响神经元功能和存活的潜在表型连续体。在 ALS 患者中，反应性星形胶质细胞环绕着上下退化的运动神经元，并在病理学中发挥着关键作用。很明显，星形胶质细胞在 ALS 病理学中起着重要作用。通过丧失正常功能或获得新特性，星形胶质细胞能够影响运动神经元的命运和疾病的进展。使用不同的细胞培养模型表明，ALS-星形胶质细胞能够通过分泌可溶性因子诱导运动神经元死亡。在这里，我们讨论了几种已提出的解释 ALS 中星形胶质细胞介导的运动神经元死亡的发病机制。此外，还回顾了逆转星形胶质细胞介导的运动神经元毒性的策略示例，以说明星形胶质细胞在 ALS 中的治疗潜力。由于星形胶质细胞在 ALS 病理学中起着核心作用，因此旨在调节星形胶质细胞生物学的疗法可能有助于开发整体治疗方法来阻止 ALS 的进展。
