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Article

Hexameric Aggregation Nucleation Core Sequences and Diversity of Pathogenic Tau Strains

1
Biomanufacturing Research Institute and Technology Enterprise (BRITE), Department of Pharmaceutical Sciences, North Carolina Central University, Durham, NC 27707, USA
2
Duke/UNC Alzheimer’s Disease Research Center, Durham, NC 27710, USA
3
Department of Biochemistry, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA
4
School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA
*
Author to whom correspondence should be addressed.
Pathogens 2022, 11(12), 1559; https://doi.org/10.3390/pathogens11121559
Submission received: 27 September 2022 / Revised: 12 December 2022 / Accepted: 14 December 2022 / Published: 19 December 2022
(This article belongs to the Special Issue Prions and Prion-Like Transmissible Protein Pathogens)

Abstract

Tau aggregation associates with multiple neurodegenerative diseases including Alzheimer’s disease and rare tauopathies such as Pick’s disease, progressive supranuclear palsy, and corticobasal degeneration. The molecular and structural basis of tau aggregation and related diverse misfolded tau strains are not fully understood. To further understand tau-protein aggregation mechanisms, we performed systematic truncation mutagenesis and mapped key segments of tau proteins that contribute to tau aggregation, where it was determined that microtubule binding domains R2 and R3 play critical roles. We validated that R2- or R3-related hexameric PHF6 and PHF6* peptide sequences are necessary sequences that render tau amyloidogenicity. We also determined that the consensus VQI peptide sequence is not sufficient for amyloidogenicity. We further proposed single- and dual-nucleation core-based strain classifications based on recent cryo-EM structures. We analyzed the structural environment of the hexameric peptide sequences in diverse tau strains in tauopathies that, in part, explains why the VQI consensus core sequence is not sufficient to induce tau aggregation. Our experimental work and complementary structural analysis highlighted the indispensible roles of the hexameric core sequences, and shed light on how the interaction environment of these core sequences contributes to diverse pathogenic tau-strains formation in various tauopathy brains.
Keywords: tau aggregation; tauopathies; nucleation core sequences; amyloidogenicity; tau strains diversity tau aggregation; tauopathies; nucleation core sequences; amyloidogenicity; tau strains diversity

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MDPI and ACS Style

Wu, L.; Madhavan, S.S.; Tan, C.; Xu, B. Hexameric Aggregation Nucleation Core Sequences and Diversity of Pathogenic Tau Strains. Pathogens 2022, 11, 1559. https://doi.org/10.3390/pathogens11121559

AMA Style

Wu L, Madhavan SS, Tan C, Xu B. Hexameric Aggregation Nucleation Core Sequences and Diversity of Pathogenic Tau Strains. Pathogens. 2022; 11(12):1559. https://doi.org/10.3390/pathogens11121559

Chicago/Turabian Style

Wu, Ling, Sidharth S. Madhavan, Christopher Tan, and Bin Xu. 2022. "Hexameric Aggregation Nucleation Core Sequences and Diversity of Pathogenic Tau Strains" Pathogens 11, no. 12: 1559. https://doi.org/10.3390/pathogens11121559

APA Style

Wu, L., Madhavan, S. S., Tan, C., & Xu, B. (2022). Hexameric Aggregation Nucleation Core Sequences and Diversity of Pathogenic Tau Strains. Pathogens, 11(12), 1559. https://doi.org/10.3390/pathogens11121559

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