A metabolite extracted from Escherichia coli suppresses tau aggregation.

Tau aggregation is a key pathological feature of neurodegenerative diseases termed tauopathies. Identifying the various cellular factors that function to prevent tau aggregation in cells can generate key insights into how to mitigate diseases associated with protein misfolding. During an investigation into developing purification methods for the protein tau, we observed that isolates of Escherichia coli lysate prevented human tau aggregation in vitro. Fractionation of the lysate was used to further isolate a small molecular weight inhibitory fraction containing multiple components, as determined by mass spectrometry and nuclear magnetic resonance. A putative inhibitory component, methylphosphonic acid (MePn), decreased tau amyloid formation when supplemented to in vitro aggregation assays. MePn also blocked the aggregation of expressed tau in live E. coli when supplemented to the culture media. Our findings can be directly applied to optimizing the purification of recombinant tau protein and, more broadly, highlight the potential of cellular metabolites to directly modulate tau amyloid formation.