Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA, 02115, USA.
Cell Death Differ. 2018 Mar;25(4):648-662. doi: 10.1038/s41418-018-0060-4. Epub 2018 Feb 19.
Although amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, was first described in 1874, a flurry of genetic discoveries in the last 10 years has markedly increased our understanding of this disease. These findings have not only enhanced our knowledge of mechanisms leading to ALS, but also have revealed that ALS shares many genetic causes with another neurodegenerative disease, frontotemporal lobar dementia (FTLD). In this review, we survey how recent genetic studies have bridged our mechanistic understanding of these two related diseases and how the genetics behind ALS and FTLD point to complex disorders, implicating non-neuronal cell types in disease pathophysiology. The involvement of non-neuronal cell types is consistent with a non-cell autonomous component in these diseases. This is further supported by studies that identified a critical role of immune-associated genes within ALS/FTLD and other neurodegenerative disorders. The molecular functions of these genes support an emerging concept that various non-autonomous functions are involved in neurodegeneration. Further insights into such a mechanism(s) will ultimately lead to a better understanding of potential routes of therapeutic intervention. Facts ALS and FTLD are severe neurodegenerative disorders on the same disease spectrum. Multiple cellular processes including dysregulation of RNA homeostasis, imbalance of proteostasis, contribute to ALS/FTLD pathogenesis. Aberrant function in non-neuronal cell types, including microglia, contributes to ALS/FTLD. Strong neuroimmune and neuroinflammatory components are associated with ALS/FTLD patients. Open Questions Why can patients with similar mutations have different disease manifestations, i.e., why do C9ORF72 mutations lead to motor neuron loss in some patients while others exhibit loss of neurons in the frontotemporal lobe? Do ALS causal mutations result in microglial dysfunction and contribute to ALS/FTLD pathology? How do microglia normally act to mitigate neurodegeneration in ALS/FTLD? To what extent do cellular signaling pathways mediate non-cell autonomous communications between distinct central nervous system (CNS) cell types during disease? Is it possible to therapeutically target specific cell types in the CNS?
虽然肌萎缩侧索硬化症（ALS），也称为葛雷克氏症，于 1874 年首次被描述，但在过去 10 年中，一系列遗传发现极大地提高了我们对这种疾病的认识。这些发现不仅增强了我们对导致 ALS 的机制的了解，还揭示了 ALS 与另一种神经退行性疾病额颞叶痴呆（FTLD）有许多共同的遗传原因。在这篇综述中，我们调查了最近的遗传研究如何弥合我们对这两种相关疾病的机制理解，以及 ALS 和 FTLD 的遗传学如何指向复杂的疾病，暗示非神经元细胞类型在疾病病理生理学中的作用。非神经元细胞类型的参与与这些疾病中的非细胞自主成分一致。这进一步得到了研究的支持，这些研究确定了免疫相关基因在 ALS/FTLD 及其他神经退行性疾病中的关键作用。这些基因的分子功能支持了一个新兴的概念，即各种非自主功能参与神经退行性变。对这种机制的进一步了解最终将导致更好地理解潜在的治疗干预途径。
事实 ALS 和 FTLD 是同一疾病谱上的严重神经退行性疾病。多种细胞过程，包括 RNA 稳态的失调、蛋白质平衡的失衡，导致 ALS/FTLD 的发病机制。非神经元细胞类型（包括小胶质细胞）的异常功能导致 ALS/FTLD。强烈的神经免疫和神经炎症成分与 ALS/FTLD 患者相关。
开放性问题 为什么具有相似突变的患者会有不同的疾病表现，即为什么 C9ORF72 突变会导致一些患者的运动神经元丢失，而另一些患者则表现出额颞叶神经元丢失？ALS 致病突变是否导致小胶质细胞功能障碍并导致 ALS/FTLD 病理？小胶质细胞通常如何在 ALS/FTLD 中发挥作用来减轻神经退行性变？细胞信号通路在疾病过程中在多大程度上介导不同中枢神经系统（CNS）细胞类型之间的非细胞自主通讯？是否有可能在治疗上针对中枢神经系统中的特定细胞类型？
