Structural basis of the interplay between ?-synuclein and Tau in regulating pathological amyloid aggregation.

Amyloid aggregation of pathological proteins is closely associated with a variety of neurodegenerative diseases, and ?-synuclein (?-syn) deposition and Tau tangles are considered hallmarks of Parkinson's disease and Alzheimer's disease, respectively. Intriguingly, ?-syn and Tau have been found to co-deposit in the brains of individuals with dementia and parkinsonism, suggesting ...
a potential role of cross-talk between these two proteins in neurodegenerative pathologies. Here we show that monomeric ?-syn and the two variants of Tau, Tau23 and K19, synergistically promote amyloid fibrillation, leading to their co-aggregation in vitro NMR spectroscopy experiments revealed that ?-syn uses its highly negatively charged C terminus to directly interact with Tau23 and K19. Deletion of the C terminus effectively abolished its binding to Tau23 and K19 as well as its synergistic effect on promoting their fibrillation. Moreover, an S129D substitution of ?-syn, mimicking C-terminal phosphorylation of Ser129 in ?-syn, which is commonly observed in the brains of Parkinson's disease patients with elevated ?-syn phosphorylation levels, significantly enhanced the activity of ?-syn in facilitating Tau23 and K19 aggregation. These results reveal the molecular basis underlying the direct interaction between ?-syn and Tau. We proposed that this interplay might contribute to pathological aggregation of ?-syn and Tau in neurodegenerative diseases.
Mesh Terms:
Amino Acid Substitution, Amyloid, Brain, Humans, Mutation, Missense, Nuclear Magnetic Resonance, Biomolecular, Parkinson Disease, Protein Aggregates, alpha-Synuclein, tau Proteins
J Biol Chem
Date: Dec. 22, 2019
Download Curated Data For This Publication
231678
Switch View:
  • Interactions 1