Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that results from many diverse genetic causes. Although therapeutics specifically targeting known causal mutations may rescue individual types of ALS, these approaches cannot treat most cases since they have unknown genetic etiology. Thus, there is a pressing need for therapeutic strategies that rescue multiple forms of ALS. Here, we show that pharmacological inhibition of PIKFYVE kinase activates an unconventional protein clearance mechanism involving exocytosis of aggregation-prone proteins. Reducing PIKFYVE activity ameliorates ALS pathology and extends survival of animal models and patient-derived motor neurons representing diverse forms of ALS including C9ORF72, TARDBP, FUS, and sporadic. These findings highlight a potential approach for mitigating ALS pathogenesis that does not require stimulating macroautophagy or the ubiquitin-proteosome system.

肌萎缩侧索硬化症 (ALS) 是一种致命的神经退行性疾病，由多种遗传原因引起。尽管专门针对已知致病突变的疗法可能会挽救个别类型的 ALS，但这些方法无法治疗大多数病例，因为它们的遗传病因未知。因此，迫切需要挽救多种形式的 ALS 的治疗策略。在这里，我们证明 PIKFYVE 激酶的药理抑制会激活一种非常规的蛋白质清除机制，涉及易于聚集的蛋白质的胞吐作用。降低 PIKFYVE 活性可改善 ALS 病理并延长动物模型和患者来源的运动神经元的存活时间，这些运动神经元代表不同形式的 ALS，包括C9ORF72、TARDBP、FUS和散发性。这些发现强调了一种减轻 ALS 发病机制的潜在方法，该方法不需要刺激巨自噬或泛素-蛋白酶体系统。