Fluorescent timer-based screening of protein turnover modulators in human neurons

Dembska, J.; Mahul-Mellier, A.-L.; Tollenaere, A.; Jasiqi, Y.; Suter, D. M.

doi:10.64898/2026.05.06.723176

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bioRxiv · 10.64898/2026.05.06.723176

Fluorescent timer-based screening of protein turnover modulators in human neurons

Dembska, J.·Mahul-Mellier, A.-L.·Tollenaere, A.·Jasiqi, Y.·Suter, D. M.

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Abstract

Disturbances in protein homeostasis are a defining feature of aging and neurodegenerative diseases. However, current proteomics approaches do not enable screening-scale pharmacological interrogation of protein turnover in post-mitotic human neurons. Here we establish a Mammalian Cell-optimized Fluorescent Timer (MCFT)-based live-cell imaging platform to quantify global protein synthesis and degradation rates in human embryonic stem cell-derived neurons at screening scale. Among 5,897 tested compounds, 199 increased protein synthesis and degradation rates, and three selected compounds upregulated translation-associated genes in human neurons. We then tested their ability to suppress the accumulation of pathogenic -synuclein aggregates in models of Lewy body-like pathology. All three compounds induced efficient clearance of -synuclein aggregates in mouse primary neurons, and one compound demonstrated similar efficacy in human dopaminergic neurons. This platform provides a broadly applicable strategy for identifying biomedically-relevant compounds that enhance protein turnover across pluripotent stem cell-derived cellular models.

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Dembska, J., Mahul-Mellier, A.-L., Tollenaere, A., Jasiqi, Y., Suter, D. M.. 2026-05-07. Fluorescent timer-based screening of protein turnover modulators in human neurons. https://doi.org/10.64898/2026.05.06.723176

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