Language
English
Publication Date
3-3-2026
Journal
Nature Communications
DOI
10.1038/s41467-026-69618-3
PMID
41771869
PMCID
PMC13065850
PubMedCentral® Posted Date
3-3-2026
PubMedCentral® Full Text Version
Post-print
Abstract
Proteins undergo phase separation to form membraneless condensates that spatially organize biomolecular interactions. These condensates can support cellular physiology or instigate pathological protein aggregation. Tau and α-synuclein (αSyn) are neuronal proteins that form heterotypic Tau:αSyn condensates associated with physiological and pathological processes. Tau and αSyn regulate microtubules, but also misfold and co-deposit in aggregates linked to neurodegenerative disease, highlighting the ambivalent impact of Tau:αSyn condensation in health and disease. Here, we show that Tubulin modulates Tau:αSyn condensates by promoting microtubule interactions and inhibiting homotypic and heterotypic pathological oligomers. In the absence of Tubulin, Tau-driven condensation accelerates formation of pathogenic Tau:αSyn heterodimers and amyloid fibrils. Tubulin partitioning into condensates promotes microtubule polymerization and prevents Tau and αSyn oligomerization. We identify distinct Tau and αSyn structural states in pathological Tubulin-absent versus physiological Tubulin-rich condensates. In neuronal models, microtubule loss drives pathological oligomer formation and neurite loss, whereas inducible Tau condensation stabilizes microtubules.
Keywords
alpha-Synuclein, tau Proteins, Tubulin, Microtubules, Humans, Animals, Neurons, Protein Multimerization, Protein Aggregation, Pathological, Biomolecular Condensates, Amyloid, Intrinsically disordered proteins, Cellular neuroscience, Protein aggregation, Microtubules
Published Open-Access
yes
Recommended Citation
Lucas, Lathan; Tsoi, Phoebe S; Quan, My Diem; et al., "Tubulin Transforms Tau and α-Synuclein Condensates From Pathological to Physiological" (2026). Faculty, Staff and Students Publications. 8039.
https://digitalcommons.library.tmc.edu/baylor_docs/8039