Tubulin transforms Tau and α-synuclein condensates from pathological to physiological

In laboratory-grown nerve cells, reducing α-tubulin protein levels increases hyperphosphorylated Tau protein aggregates by more than five times, directly connecting microtubule breakdown to a hallmark feature of tauopathy diseases.

In neurons, using light-controlled tools to cluster Tau proteins rebuilds the internal transport structures called microtubules even when they are damaged by disease conditions, showing that these Tau clusters act as physical platforms for microtubule formation.

In laboratory protein mixtures, tubulin changes the shape of Tau:αSyn protein clusters from round droplets to elongated structures, which decreases the formation of harmful protein aggregates by encouraging tubulin to form microtubules and keeping both proteins in extended shapes.

Tubulin binding changes the shape of Tau and α-synuclein proteins inside cellular condensates, shifting them from tightly packed forms prone to aggregation to more extended forms that can interact with microtubules, as measured by fluorescence lifetime and FRET efficiency in laboratory experiments.

When microtubules in nerve cells break down due to lack of tubulin or oxidative damage, nerve projections shrink and Tau and α-synuclein proteins accumulate together in abnormal clusters.