Brites Dora, Vaz Ana R
Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa Lisbon, Portugal ; Department of Biochemistry and Human Biology, Faculdade de Farmácia, Universidade de Lisboa Lisbon, Portugal.
Front Cell Neurosci. 2014 May 22;8:117. doi: 10.3389/fncel.2014.00117. eCollection 2014.
Amyotrophic lateral sclerosis (ALS) is the most common and most aggressive form of adult motor neuron (MN) degeneration. The cause of the disease is still unknown, but some protein mutations have been linked to the pathological process. Loss of upper and lower MNs results in progressive muscle paralysis and ultimately death due to respiratory failure. Although initially thought to derive from the selective loss of MNs, the pathogenic concept of non-cell-autonomous disease has come to the forefront for the contribution of glial cells in ALS, in particular microglia. Recent studies suggest that microglia may have a protective effect on MN in an early stage. Conversely, activated microglia contribute and enhance MN death by secreting neurotoxic factors, and impaired microglial function at the end-stage may instead accelerate disease progression. However, the nature of microglial-neuronal interactions that lead to MN degeneration remains elusive. We review the contribution of the neurodegenerative network in ALS pathology, with a special focus on each glial cell type from data obtained in the transgenic SOD1G93A rodents, the most widely used model. We further discuss the diverse roles of neuroinflammation and microglia phenotypes in the modulation of ALS pathology. We provide information on the processes associated with dysfunctional cell-cell communication and summarize findings on pathological cross-talk between neurons and astroglia, and neurons and microglia, as well as on the spread of pathogenic factors. We also highlight the relevance of neurovascular disruption and exosome trafficking to ALS pathology. The harmful and beneficial influences of NG2 cells, oligodendrocytes and Schwann cells will be discussed as well. Insights into the complex intercellular perturbations underlying ALS, including target identification, will enhance our efforts to develop effective therapeutic approaches for preventing or reversing symptomatic progression of this devastating disease.
肌萎缩侧索硬化症（ALS）是成人运动神经元（MN）变性最常见且最具侵袭性的形式。该疾病的病因仍不清楚，但一些蛋白质突变已与病理过程相关联。上下运动神经元的丧失导致进行性肌肉麻痹，并最终因呼吸衰竭而死亡。尽管最初认为源于运动神经元的选择性丧失，但非细胞自主疾病的致病概念已因胶质细胞，特别是小胶质细胞在ALS中的作用而成为前沿研究内容。最近的研究表明，小胶质细胞在早期可能对运动神经元具有保护作用。相反，活化的小胶质细胞通过分泌神经毒性因子促进并加剧运动神经元死亡，而末期小胶质细胞功能受损可能反而加速疾病进展。然而，导致运动神经元变性的小胶质细胞 - 神经元相互作用的本质仍然难以捉摸。我们回顾了神经退行性网络在ALS病理学中的作用，特别关注从转基因SOD1G93A啮齿动物（最广泛使用的模型）获得的数据中每种胶质细胞类型的作用。我们进一步讨论神经炎症和小胶质细胞表型在调节ALS病理学中的不同作用。我们提供与功能失调的细胞间通讯相关的过程信息，并总结神经元与星形胶质细胞、神经元与小胶质细胞之间病理相互作用以及致病因子传播的研究结果。我们还强调神经血管破坏和外泌体运输与ALS病理学的相关性。此外，还将讨论NG2细胞、少突胶质细胞和雪旺细胞的有害和有益影响。深入了解ALS潜在的复杂细胞间扰动，包括靶点识别，将增强我们开发有效治疗方法以预防或逆转这种毁灭性疾病症状进展的努力。
