PIKFYVE inhibition mitigates disease in models of diverse forms of ALS

• Published in: Cell Vol. 186; no. 4; pp. 786 - 802.e28
• Main Authors: Hung, Shu-Ting, Linares, Gabriel R., Chang, Wen-Hsuan, Eoh, Yunsun, Krishnan, Gopinath, Mendonca, Stacee, Hong, Sarah, Shi, Yingxiao, Santana, Manuel, Kueth, Chuol, Macklin-Isquierdo, Samantha, Perry, Sarah, Duhaime, Sarah, Maios, Claudia, Chang, Jonathan, Perez, Joscany, Couto, Alexander, Lai, Jesse, Li, Yichen, Alworth, Samuel V., Hendricks, Eric, Wang, Yaoming, Zlokovic, Berislav V., Dickman, Dion K., Parker, J. Alex, Zarnescu, Daniela C., Gao, Fen-Biao, Ichida, Justin K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16-02-2023
• Subjects: ALS; Amyotrophic Lateral Sclerosis - drug therapy; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Animals; Disease Models, Animal; Motor Neurons; Mutation; neurodegeneration; Phosphatidylinositol 3-Kinases - metabolism; PIKFYVE; RNA-Binding Protein FUS - metabolism; ALS; neurodegeneration; PIKFYVE
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2023.01.005

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.
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•PIKFYVE inhibition mitigates disease in iPSC and animal models of diverse forms of ALS•PIKFYVE inhibition clears aggregation-prone proteins via exocytosis•Pikfyve suppression reduces pathology and extends survival of ALS mouse models•Chronic reduction of PIKFYVE activity is well tolerated and efficacious in TDP-43 mice
Pharmacological reduction of PIKFYVE kinase activity activates an unconventional protein clearance mechanism involving exocytosis of aggregation-prone proteins that mitigates disease in diverse models of ALS.