Shu-Ting Hung et al
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that can result from a variety of genetic causes. Although therapeutics specifically targeting known causal mutations may benefit patients, these approaches cannot treat most with an unknown genetic etiology. Since the accumulation of misfolded proteins is common to all patients with ALS, researchers considered whether activating exocytosis might increase induced motor neuron (iMN) survival for diverse forms of ALS. PIKFYVE inhibition stimulates the exocytosis of neurotoxic proteins from iMNs of patients with ALS, reduces intracellular pathology, and increases TAR DNA-binding protein 43 (TDP-43) splicing activity. Thus, activating the exocytosis of pathological proteins from neurons mitigates disease in models representing diverse forms of ALS. Reducing PIKFYVE activity was found to ameliorate ALS pathology and extend survival of animal models and patient-derived motor neurons representing diverse forms of ALS including C9ORF72, TARDBP, FUS, and sporadic. The unusually broad efficacy observed across models of different forms of ALS merits further investigation into this unconventional protein clearance mechanism and its potential as a therapeutic approach.
Additional information is available on the PubMed website:
PMID: 36754049
