Department of Biology, Stanford University, Stanford, California.
Present address: Department of Biochemistry, Weill Cornell Medical College, New York, New York, USA.
Curr Opin Neurol. 2018 Dec;31(6):693-701. doi: 10.1097/WCO.0000000000000621.
The current review analyzes recent findings that suggest that axon degeneration is a druggable process in the treatment of neurodegenerative disorders and a subset of traumas.
Emerging evidence reveals that axon degeneration is an active and regulated process in the early progression of some neurodegenerative diseases and acute traumas, which is orchestrated through a combination of axon-intrinsic and somatically derived signaling events. The identification of these pathways has presented appealing drug targets whose specificity for the nervous system and phenotypes in mouse models offers significant clinical opportunity.
As the biology of axon degeneration becomes clear, so too has the realization that the pathways driving axon degeneration overlap in part with those that drive neuronal apoptosis and, importantly, axon regeneration. Axon-specific disorders like those seen in CIPN, where injury signaling to the nucleus is not a prominent feature, have been shown to benefit from disruption of Sarm1. In injury and disease contexts, where involvement of somatic events is prominent, inhibition of the MAP Kinase DLK exhibits promise for neuroprotection. Here, however, interfering with somatic signaling may preclude the ability of an axon or a circuit to regenerate or functionally adapt following acute injuries.
本综述分析了最近的研究结果，这些结果表明，轴突退化是神经退行性疾病和部分创伤治疗中的一个可药物干预的过程。
新出现的证据表明，轴突退化是一些神经退行性疾病和急性创伤早期进展中的一个主动和受调控的过程，这是通过轴突内在和躯体衍生的信号事件的组合来协调的。这些途径的确定提出了有吸引力的药物靶点，这些靶点在神经系统中的特异性和小鼠模型中的表型为临床应用提供了重要机会。
随着轴突退化生物学的发展，人们越来越认识到，驱动轴突退化的途径与驱动神经元凋亡的途径部分重叠，重要的是，与轴突再生的途径重叠。像 CIPN 中那样的轴突特异性疾病，其中对细胞核的损伤信号不是一个突出的特征，已经显示出受益于 Sarm1 的破坏。在损伤和疾病的情况下，躯体事件的参与是明显的，抑制 MAP 激酶 DLK 显示出神经保护的希望。然而，在这里，干扰躯体信号可能会阻止轴突或回路在急性损伤后再生或功能适应的能力。
