John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Robinson Way, Cambridge, CB2 0PY, UK.
Neurotherapeutics. 2022 Jul;19(4):1133-1144. doi: 10.1007/s13311-022-01297-6. Epub 2022 Oct 7.
This review addresses the longstanding debate over whether amyotrophic lateral sclerosis (ALS) is a 'dying back' or 'dying forward' disorder in the light of new gene identifications and the increased understanding of mechanisms of action for previously identified ALS genes. While the topological pattern of pathology in animal models, and more anecdotally in patients is indeed 'dying back', this review discusses how this fits with the fact that many of the major initiating events are thought to occur within the soma. It also discusses how widely varying ALS risk factors, including some impacting axons directly, may combine to drive a common pathway involving TAR DNA binding protein 43 (TDP-43) and neuromuscular junction (NMJ) denervation. The emerging association between sterile alpha and TIR motif-containing 1 (SARM1), a protein so far mostly associated with axon degeneration, and sporadic ALS is another major theme. The strengths and limitations of the current evidence supporting an association are considered, along with ways in which SARM1 could become activated in ALS. The final section addresses SARM1-based therapies along with the prospects for targeting other axonal steps in ALS pathogenesis.
这篇综述根据新的基因鉴定和对先前鉴定的 ALS 基因作用机制的深入了解，探讨了肌萎缩侧索硬化症 (ALS) 是否为“退行性”或“进行性”疾病这一长期存在的争议。虽然动物模型中的病理学拓扑模式，更具体地说是在患者中，确实是“退行性”的，但这篇综述讨论了这如何与这样一个事实相吻合，即许多主要的起始事件被认为发生在体部。它还讨论了广泛的不同的 ALS 风险因素，包括一些直接影响轴突的因素，如何结合起来驱动一条共同的通路，涉及 TAR DNA 结合蛋白 43（TDP-43）和神经肌肉接头（NMJ）去神经支配。无菌 alpha 和 TIR 基序包含蛋白 1（SARM1）与散发性 ALS 之间的新关联是另一个主要主题。考虑了目前支持关联的证据的优缺点，以及 SARM1 在 ALS 中如何被激活。最后一节讨论了基于 SARM1 的治疗方法以及针对 ALS 发病机制中其他轴突步骤的靶向治疗的前景。
