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

• Published in: The Journal of biological chemistry Vol. 295; no. 21; pp. 7470 - 7480
• Main Authors: Lu, Jinxia, Zhang, Shengnan, Ma, Xiaojuan, Jia, Chunyu, Liu, Zhenying, Huang, Chengan, Liu, Cong, Li, Dan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.05.2020; American Society for Biochemistry and Molecular Biology
• Subjects: aggregation; alpha-Synuclein - chemistry; alpha-Synuclein - genetics; alpha-Synuclein - metabolism; Alzheimer's disease; Amino Acid Substitution; amyloid; Amyloid - chemistry; Amyloid - genetics; Amyloid - metabolism; Brain - metabolism; dementia; fibril; Humans; Lewy body; Molecular Biophysics; Mutation, Missense; neurodegeneration; Nuclear Magnetic Resonance, Biomolecular; Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson's disease; Protein Aggregates; protein misfolding; Tau protein (Tau); tau Proteins - chemistry; tau Proteins - genetics; tau Proteins - metabolism; α-synuclein; fibril; amyloid; Parkinson's disease; Tau protein (Tau); protein misfolding; neurodegeneration; dementia; aggregation; Alzheimer's disease; α-synuclein; Lewy body
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.RA119.012284

Amyloid aggregation of pathological proteins is closely associated with a variety of neurodegenerative diseases, and α-synuclein (α-syn) deposition and Tau tangles are considered hallmarks of Parkinson's disease and Alzheimer's disease, respectively. Intriguingly, α-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 α-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 α-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 α-syn, mimicking C-terminal phosphorylation of Ser129 in α-syn, which is commonly observed in the brains of Parkinson's disease patients with elevated α-syn phosphorylation levels, significantly enhanced the activity of α-syn in facilitating Tau23 and K19 aggregation. These results reveal the molecular basis underlying the direct interaction between α-syn and Tau. We proposed that this interplay might contribute to pathological aggregation of α-syn and Tau in neurodegenerative diseases.