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Updated: Aug 11, 2025
Real-Time Fluorescent Measurement of Synaptic Functions in Models of Amyotrophic Lateral Sclerosis
Published on: July 16, 2021
PIKFYVE inhibition mitigates disease in models of diverse forms of ALS
Shu-Ting Hung1, Gabriel R Linares1, Wen-Hsuan Chang2
1Department 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.
Abstract:
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.
Insights
Inhibiting PIKFYVE kinase clears toxic proteins in amyotrophic lateral sclerosis (ALS). This approach benefits diverse ALS forms, offering a new therapeutic avenue beyond traditional pathways.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with diverse genetic causes.
- Current ALS therapies targeting specific mutations are ineffective for most patients with unknown genetic origins.
- A need exists for broad-acting therapeutic strategies for ALS.
Purpose of the Study:
- To investigate the potential of pharmacological inhibition of PIKFYVE kinase as a therapeutic strategy for ALS.
- To determine if targeting PIKFYVE kinase can activate unconventional protein clearance mechanisms.
- To evaluate the efficacy of reducing PIKFYVE activity in diverse models of ALS.
Main Methods:
- Pharmacological inhibition of PIKFYVE kinase.
- Assessing protein clearance via exocytosis.
- Utilizing animal models and patient-derived motor neurons representing various ALS genetic subtypes (C9ORF72, TARDBP, FUS) and sporadic ALS.
Main Results:
- PIKFYVE kinase inhibition activates an unconventional protein clearance pathway involving exocytosis.
- Reduced PIKFYVE activity ameliorates ALS pathology in diverse models.
- Therapeutic intervention extended survival in animal models and patient-derived motor neurons.
Conclusions:
- Pharmacological inhibition of PIKFYVE kinase represents a promising therapeutic strategy for multiple forms of ALS.
- This approach activates a novel protein clearance mechanism distinct from macroautophagy or the ubiquitin-proteasome system.
- Targeting PIKFYVE offers a potential treatment for a wide range of ALS cases, including sporadic forms.
