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

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.
Competing Interests: 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.
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