A phenotypic screen for novel small molecules that correct tau-mediated pathologies in human frontotemporal dementia neurons.

Introduction: Mutations in the MAPT gene that are causal for frontotemporal dementia (FTD) lead to mislocalization of tau protein to the neuronal cell body, changing microtubule dynamics to disrupt the nuclear envelope and nucleocytoplasmic transport.

Methods: We report a high content imaging-based phenotypic screen to identify novel small molecules that correct nuclear envelope defects in human neurons expressing the MAPT IVS10+16 mutation causal for FTD.

Results: Screening a 19,786-compound chemical diversity library, we identified > 100 compounds that corrected nuclear membrane defects in MAPT IVS10+16 neurons, with 23 demonstrating robust dose-dependent rescue. A common feature of hit compounds was alteration of the neuronal microtubule cytoskeleton, with a subset changing neuronal tau protein levels or phosphorylation.

Discussion: Human models of tauopathy were used in a phenotypic screen to identify novel chemotypes that correct a validated pathology, illustrating the value of human models of neurodegenerative disease in the drug discovery process.

Highlights: A phenotypic screen for novel small molecules that suppress tau-mediated pathologies was carried out in human frontotemporal dementia neurons. The key readout was correction of nuclear membrane defects, which are a pathological feature in tauopathies in vivo. The screen of 20,000 small molecules identified more than 20 compounds that corrected the phenotype in a dose-dependent manner. Hit compounds commonly altered microtubules, with a subset changing tau protein levels or phosphorylation.