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Structural basis of the interplay between α-synuclein and Tau in regulating pathological amyloid aggregation.
J Biol Chem. 2020 05 22; 295(21):7470-7480.JB

Abstract

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 Ser[129] 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.

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Authors+Show Affiliations

Lu J
Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China.
Zhang S
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 26 Qiuyue Road, Shanghai 201210, China.
Ma X
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 26 Qiuyue Road, Shanghai 201210, China; University of the Chinese Academy of Sciences, 19 A Yuquan Road, Shijingshan District, Beijing 100049, China.
Jia C
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 26 Qiuyue Road, Shanghai 201210, China; University of the Chinese Academy of Sciences, 19 A Yuquan Road, Shijingshan District, Beijing 100049, China.
Liu Z
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 26 Qiuyue Road, Shanghai 201210, China; University of the Chinese Academy of Sciences, 19 A Yuquan Road, Shijingshan District, Beijing 100049, China.
Huang C
Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China.
Liu C
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 26 Qiuyue Road, Shanghai 201210, China. Electronic address: liulab@sioc.ac.cn.
Li D
Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China. Electronic address: lidan2017@sjtu.edu.cn.

MeSH

Amino Acid SubstitutionAmyloidBrainHumansMutation, MissenseNuclear Magnetic Resonance, BiomolecularParkinson DiseaseProtein Aggregatesalpha-Synucleintau Proteins

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32291284

Citation

Lu, Jinxia, et al. "Structural Basis of the Interplay Between Α-synuclein and Tau in Regulating Pathological Amyloid Aggregation." The Journal of Biological Chemistry, vol. 295, no. 21, 2020, pp. 7470-7480.
Lu J, Zhang S, Ma X, et al. Structural basis of the interplay between α-synuclein and Tau in regulating pathological amyloid aggregation. J Biol Chem. 2020;295(21):7470-7480.
Lu, J., Zhang, S., Ma, X., Jia, C., Liu, Z., Huang, C., Liu, C., & Li, D. (2020). Structural basis of the interplay between α-synuclein and Tau in regulating pathological amyloid aggregation. The Journal of Biological Chemistry, 295(21), 7470-7480. https://doi.org/10.1074/jbc.RA119.012284
Lu J, et al. Structural Basis of the Interplay Between Α-synuclein and Tau in Regulating Pathological Amyloid Aggregation. J Biol Chem. 2020 05 22;295(21):7470-7480. PubMed PMID: 32291284.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structural basis of the interplay between α-synuclein and Tau in regulating pathological amyloid aggregation. AU - Lu,Jinxia, AU - Zhang,Shengnan, AU - Ma,Xiaojuan, AU - Jia,Chunyu, AU - Liu,Zhenying, AU - Huang,Chengan, AU - Liu,Cong, AU - Li,Dan, Y1 - 2020/04/13/ PY - 2019/12/11/received PY - 2020/04/04/revised PY - 2020/4/16/pubmed PY - 2020/12/29/medline PY - 2020/4/16/entrez KW - Alzheimer's disease KW - Lewy body KW - Parkinson's disease KW - Tau protein (Tau) KW - aggregation KW - amyloid KW - dementia KW - fibril KW - neurodegeneration KW - protein misfolding KW - α-synuclein SP - 7470 EP - 7480 JF - The Journal of biological chemistry JO - J Biol Chem VL - 295 IS - 21 N2 - 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 Ser[129] 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. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/32291284/Structural_basis_of_the_interplay_between_α_synuclein_and_Tau_in_regulating_pathological_amyloid_aggregation_ DB - PRIME DP - Unbound Medicine ER -