Disarm Therapeutics, a wholly owned subsidiary of Eli Lilly & Co, Cambridge, MA 02142, USA.
Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
Cell Rep. 2021 Jan 5;34(1):108588. doi: 10.1016/j.celrep.2020.108588.
Axonal degeneration is responsible for disease progression and accumulation of disability in many neurodegenerative conditions. The axonal degenerative process can generate a metastable pool of damaged axons that remain structurally and functionally viable but fated to degenerate in the absence of external intervention. SARM1, an NADase that depletes axonal energy stores upon activation, is the central driver of an evolutionarily conserved program of axonal degeneration. We identify a potent and selective small molecule isoquinoline inhibitor of SARM1 NADase that recapitulates the SARM1 phenotype and protects axons from degeneration induced by axotomy or mitochondrial dysfunction. SARM1 inhibition post-mitochondrial injury with rotenone allows recovery and rescues axons that already entered the metastable state. We conclude that SARM1 inhibition with small molecules has the potential to treat axonopathies of the central and peripheral nervous systems by preventing axonal degeneration and by allowing functional recovery of a metastable pool of damaged, but viable, axons.
轴突变性是许多神经退行性疾病进展和残疾积累的原因。轴突变性过程会产生一个不稳定的损伤轴突池，这些轴突在结构和功能上仍然存活，但如果没有外部干预，它们注定会退化。SARM1 是一种 NADase，在激活时耗尽轴突的能量储备，是轴突退化的进化保守程序的核心驱动因素。我们鉴定出一种有效的、选择性的小分子异喹啉 SARM1 NADase 抑制剂，它能重现 SARM1 表型，并能防止轴突因切割或线粒体功能障碍而退化。在 rotenone 引起线粒体损伤后抑制 SARM1 可恢复并挽救已进入不稳定状态的轴突。我们得出结论，小分子抑制 SARM1 有可能通过防止轴突变性和允许受损但存活的轴突的稳定状态池的功能恢复来治疗中枢和周围神经系统的轴突病。
