Cancer Prevention and Research Institute of Texas (CPRIT)
RP220582
米国
National Institutes of Health/National Institute of Mental Health (NIH/NIMH)
1RF1AG065407-01A1
米国
Chan Zuckerberg Initiative
2018-191983 (5022)
米国
引用
ジャーナル: Sci Adv / 年: 2025 タイトル: Functional classification of tauopathy strains reveals the role of protofilament core residues. 著者: Jaime Vaquer-Alicea / Victor A Manon / Vaibhav Bommareddy / Peter Kunach / Ankit Gupta / Jim Monistrol / Valerie A Perez / Hung Tri Tran / Nil Saez-Calveras / Siling Du / Sushobhna Batra / ...著者: Jaime Vaquer-Alicea / Victor A Manon / Vaibhav Bommareddy / Peter Kunach / Ankit Gupta / Jim Monistrol / Valerie A Perez / Hung Tri Tran / Nil Saez-Calveras / Siling Du / Sushobhna Batra / Daniel Stoddard / Charles L White / Lukasz A Joachimiak / Sarah H Shahmoradian / Marc I Diamond / 要旨: Distinct tau amyloid assemblies underlie diverse tauopathies but defy rapid classification. Cell and animal experiments indicate tau functions as a prion, as different strains propagated in cells ...Distinct tau amyloid assemblies underlie diverse tauopathies but defy rapid classification. Cell and animal experiments indicate tau functions as a prion, as different strains propagated in cells cause unique, transmissible neuropathology after inoculation. Strain amplification requires compatibility of the monomer and amyloid template. We used cryo-electron microscopy to study one cell-based yellow fluorescent protein (YFP)-tagged strain, resolving its amyloid nature. We then used sequential alanine (Ala) substitution (scan) within tau repeat domain (RD) to measure incorporation to preexisting tau RD-YFP aggregates. This robustly discriminated strains, defining sequences critical for monomer incorporation. We then created 3R/4R or 4R wild-type RD (amino acids 246 to 408) biosensors. Ala scan of recombinant tau seeds with the Alzheimer's disease (AD) fold matched that of AD homogenate. We scanned 22 brain lysates comprising four tauopathies. This clustered cases by neuropathological syndrome, revealed the role of amino acids in protofilament folds, and allowed strain discrimination based on amino acid requirements for prion replication.