Axonal degeneration and neuronal cell death are fundamental processes in development and contribute to the pathology of neurological disease in adults. Both processes are regulated by BCL-2 family proteins which orchestrate the permeabilization of the mitochondrial outer membrane (MOM). MOM permeabilization (MOMP) results in the activation of pro-apoptotic molecules that commit neurons to either die or degenerate. With the success of small-molecule inhibitors targeting anti-apoptotic BCL-2 proteins for the treatment of lymphoma, we can now envision the use of inhibitors of apoptosis with exquisite selectivity for BCL-2 family protein regulation of neuronal apoptosis in the treatment of nervous system disease. Critical to this development is deciphering which subset of proteins is required for neuronal apoptosis and axon degeneration, and how these two different outcomes are separately regulated. Moreover, noncanonical BCL-2 family protein functions unrelated to the regulation of MOMP, including impacting necroptosis and other modes of cell death may reveal additional potential targets and/or confounders. This review highlights our current understanding of BCL-2 family mediated neuronal cell death and axon degeneration, while identifying future research questions to be resolved to enable regulating neuronal survival pharmacologically.

轴索变性和神经元细胞死亡是发育过程中的基本过程，并有助于成人神经系统疾病的病理学。这两个过程都受 BCL-2 家族蛋白的调控，这些蛋白协调线粒体外膜 (MOM) 的透化。MOM 透化 (MOMP) 导致促凋亡分子的激活，使神经元死亡或退化。随着靶向抗凋亡 BCL-2 蛋白的小分子抑制剂用于治疗淋巴瘤的成功，我们现在可以设想使用对 BCL-2 家族蛋白调节神经元凋亡具有精细选择性的凋亡抑制剂用于治疗神经细胞凋亡。系统疾病。这一发展的关键是破译神经元凋亡和轴突退化所需的蛋白质子集，以及如何分别监管这两种不同的结果。此外，与 MOMP 调节无关的非经典 BCL-2 家族蛋白功能，包括影响坏死性凋亡和其他细胞死亡模式，可能会揭示其他潜在目标和/或混杂因素。这篇综述强调了我们目前对 BCL-2 家族介导的神经元细胞死亡和轴突变性的理解，同时确定了未来需要解决的研究问题，以便在药理学上调节神经元存活。