近日，美国南加州大学Justin K. Ichida及其研究团队发现PIKFYVE抑制在不同形式的ALS模型中减轻疾病。该项研究成果于2023年2月7日在线发表在《细胞》杂志上。

研究人员PIKFYVE激酶的药理学抑制激活了一种非常规的蛋白清除机制，涉及聚集倾向蛋白的胞吐。降低PIKFYVE活性可以改善肌萎缩性侧索硬化症（ALS）病理，延长动物模型和患者来源的运动神经元的生存期，这些运动神经元代表了不同形式的ALS，包括C9ORF72、TARDBP、FUS和sporadic。这些发现强调了一种不需要刺激巨自噬或泛素-蛋白质体系统就能缓解ALS发病的潜在方法。

据悉，ALS是一种致命的神经退行性疾病，由多种不同的遗传因素引起。虽然专门针对已知突变的治疗方法可能挽救个别类型的ALS，但这些方法不能治疗大多数病例，因为它们有未知的遗传病因。因此，迫切需要治疗策略来拯救多种形式的ALS。

附：英文原文

Title: PIKFYVE inhibition mitigates disease in models of diverse forms of ALS

Author: Shu-Ting Hung, Gabriel R. Linares, Wen-Hsuan Chang, Yunsun Eoh, Gopinath Krishnan, Stacee Mendonca, Sarah Hong, Yingxiao Shi, Manuel Santana, Chuol Kueth, Samantha Macklin-Isquierdo, Sarah Perry, Sarah Duhaime, Claudia Maios, Jonathan Chang, Joscany Perez, Alexander Couto, Jesse Lai, Yichen Li, Samuel V. Alworth, Eric Hendricks, Yaoming Wang, Berislav V. Zlokovic, Dion K. Dickman, J. Alex Parker, Daniela C. Zarnescu, Fen-Biao Gao, Justin K. Ichida

Issue&Volume: 2023-02-07

Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that resultsfrom many diverse genetic causes. Although therapeutics specifically targeting knowncausal mutations may rescue individual types of ALS, these approaches cannot treatmost cases since they have unknown genetic etiology. Thus, there is a pressing needfor therapeutic strategies that rescue multiple forms of ALS. Here, we show that pharmacologicalinhibition of PIKFYVE kinase activates an unconventional protein clearance mechanisminvolving exocytosis of aggregation-prone proteins. Reducing PIKFYVE activity amelioratesALS pathology and extends survival of animal models and patient-derived motor neuronsrepresenting diverse forms of ALS including C9ORF72, TARDBP, FUS, and sporadic. These findings highlight a potential approach for mitigating ALS pathogenesisthat does not require stimulating macroautophagy or the ubiquitin-proteosome system.

DOI: 10.1016/j.cell.2023.01.005

Source: https://www.cell.com/cell/fulltext/S0092-8674(23)00005-3