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

Area of Science:

• Biochemistry
• Cell Biology
• Neuroscience

Background:

• Proteins form membraneless condensates for spatial organization, impacting cellular physiology and disease.
• Tau and alpha-synuclein (αSyn) are neuronal proteins forming heterotypic condensates linked to neurodegenerative diseases.
• Tau:αSyn condensates have ambivalent roles, potentially supporting physiology or driving pathological aggregation.

Purpose of the Study:

• To investigate the role of Tubulin in modulating Tau:αSyn condensates.
• To understand how Tubulin affects Tau:αSyn condensation, oligomerization, and microtubule interactions.
• To elucidate the structural differences in Tau and αSyn within condensates under varying Tubulin conditions.

Main Methods:

• In vitro studies of Tau:αSyn condensates with and without Tubulin.
• Analysis of protein oligomerization and fibril formation.
• Neuronal models to assess the impact of Tubulin on Tau:αSyn condensation and microtubule dynamics.

Main Results:

• Tubulin inhibits homotypic and heterotypic pathological oligomers of Tau and αSyn.
• Absence of Tubulin accelerates pathogenic Tau:αSyn heterodimer and amyloid fibril formation.
• Tubulin promotes microtubule polymerization and prevents Tau and αSyn oligomerization, stabilizing neuronal structure.

Conclusions:

• Tubulin plays a critical protective role in Tau:αSyn condensates by preventing pathological aggregation.
• Distinct structural states of Tau and αSyn exist in Tubulin-dependent condensates, correlating with physiological or pathological outcomes.
• Microtubule integrity, modulated by Tubulin, is crucial for neuronal health and preventing neurodegeneration.