PIKFYVE inhibition mitigates disease in models of diverse forms of ALS

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. AlworthEric Hendricks, Yaoming Wang, Berislav V. Zlokovic, Dion K. Dickman, J. Alex Parker, Daniela C. Zarnescu, Fen Biao Gao, Justin K. Ichida

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)786-802.e28
Issue number4
StatePublished - Feb 16 2023
Externally publishedYes


  • ALS
  • neurodegeneration

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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