PIKFYVE inhibition mitigates disease in models of diverse forms of ALS.

1. Cell. 2023 Feb 16;186(4):786-802.e28. doi: 10.1016/j.cell.2023.01.005. Epub 2023 Feb 7. PIKFYVE inhibition mitigates disease in models of diverse forms of ALS. Hung ST(1), Linares GR(1), Chang WH(2), Eoh Y(1), Krishnan G(3), Mendonca S(2), Hong S(2), Shi Y(1), Santana M(1), Kueth C(4), Macklin-Isquierdo S(4), Perry S(5), Duhaime S(6), Maios C(6), Chang J(1), Perez J(1), Couto A(1), Lai J(1), Li Y(1), Alworth SV(2), Hendricks E(1), Wang Y(7), Zlokovic BV(7), Dickman DK(5), Parker JA(6), Zarnescu DC(4), Gao FB(3), Ichida JK(8). Author information: (1)Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA 90033, USA; Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA. (2)AcuraStem Incorporated, Monrovia, CA 91016, USA. (3)Department of Neurology, UMass Chan Medical School, Worcester, MA 01605, USA. (4)Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA. (5)Department of Neurobiology, University of Southern California, Los Angeles, CA 90089, USA. (6)Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Département de Pathologie et Biologie Cellulaire, Université de Montréal, Montréal, QC, Canada. (7)Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA; Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. (8)Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA 90033, USA; Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA. Electronic address: ichida@usc.edu. Erratum in Cell. 2026 Feb 5;189(3):987-992. doi: 10.1016/j.cell.2026.01.004. Comment in Nat Rev Drug Discov. 2023 Apr;22(4):268. doi: 10.1038/d41573-023-00033-9. 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. Copyright © 2023 Elsevier Inc. All rights reserved. DOI: 10.1016/j.cell.2023.01.005 PMCID: PMC10062012 PMID: 36754049 [Indexed for MEDLINE] Conflict of interest statement: Declaration of interests J.K.I. and S.-T.A. are co-founders of AcuraStem, Inc. S.-T.A., W.-H.C., S.M., and S.H. are employees of AcuraStem, Inc. J.K.I. is a co-founder of Modulo Bio, serves on the scientific advisory boards of AcuraStem, Spinogenix, Synapticure, and Vesalius Therapeutics, and is employed at BioMarin Pharmaceutical. B.V.Z. is a co-founder of ZZ Biotech and chairman of its scientific advisory board. J.A.P. is a co-founder of Modelis. F.-B.G. receives research funding from Stealth BioTherapeutics.