Variations in Filament Conformation Dictate Seeding Barrier between Three- and Four-Repeat Tau

Dinkel, Paul D.; Siddiqua, Ayisha; Huynh, Huy M.; Shah, Mubarak; Margittai, Martin

doi:10.1021/bi2004685

Cited by 86 publications

(114 citation statements)

References 48 publications

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“…The aggregates characteristic of AGD, PSP, and CBD are made of four-repeat tau, as is the human tau isoform the ALZ17 line is transgenic for. These findings agree with in vitro studies that have shown that seeds made of either three-repeat, three/four-repeat, or four-repeat tau can recruit soluble four-repeat tau (32).…”

Section: Discussionsupporting

confidence: 91%

Brain homogenates from human tauopathies induce tau inclusions in mouse brain

Clavaguera

Akatsu

Fraser

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

672

656

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Filamentous inclusions made of hyperphosphorylated tau are characteristic of numerous human neurodegenerative diseases, including Alzheimer's disease, tangle-only dementia, Pick disease, argyrophilic grain disease (AGD), progressive supranuclear palsy, and corticobasal degeneration. In Alzheimer's disease and AGD, it has been shown that filamentous tau appears to spread in a stereotypic manner as the disease progresses. We previously demonstrated that the injection of brain extracts from human mutant P301S tau-expressing transgenic mice into the brains of mice transgenic for wild-type human tau (line ALZ17) resulted in the assembly of wild-type human tau into filaments and the spreading of tau inclusions from the injection sites to anatomically connected brain regions. Here we injected brain extracts from humans who had died with various tauopathies into the hippocampus and cerebral cortex of ALZ17 mice. Argyrophilic tau inclusions formed in all cases and following the injection of the corresponding brain extracts, we recapitulated the hallmark lesions of AGD, PSP and CBD. Similar inclusions also formed after intracerebral injection of brain homogenates from human tauopathies into nontransgenic mice. Moreover, the induced formation of tau aggregates could be propagated between mouse brains. These findings suggest that once tau aggregates have formed in discrete brain areas, they become self-propagating and spread in a prion-like manner.

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Section: Discussionsupporting

confidence: 91%

Brain homogenates from human tauopathies induce tau inclusions in mouse brain

Clavaguera

Akatsu

Fraser

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

672

656

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show abstract

“…Using the recombinant K18 and K19 constructs, which encode the 4R and 3R RDs of tau, respectively, Dinkel et al (47) demonstrated that heparin-induced K19 3R aggregates could not seed filaments formed from K18 4R monomers. In a separate experiment, recombinant 1N3R or 1N4R human tau fibrils were used to test the cross-isoform prion replication barrier in the neuroblastoma cell line SH-SY5Y (48).…”

Section: Discussionmentioning

confidence: 99%

Tau prions from Alzheimer’s disease and chronic traumatic encephalopathy patients propagate in cultured cells

Woerman

Aoyagi

Patel

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

151

130

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Tau prions are thought to aggregate in the central nervous system, resulting in neurodegeneration. Among the tauopathies, Alzheimer's disease (AD) is the most common, whereas argyrophilic grain disease (AGD), corticobasal degeneration (CBD), chronic traumatic encephalopathy (CTE), Pick's disease (PiD), and progressive supranuclear palsy (PSP) are less prevalent. Brain extracts from deceased individuals with PiD, a neurodegenerative disorder characterized by three-repeat (3R) tau prions, were used to infect HEK293T cells expressing 3R tau fused to yellow fluorescent protein (YFP). Extracts from AGD, CBD, and PSP patient samples, which contain four-repeat (4R) tau prions, were transmitted to HEK293 cells expressing 4R tau fused to YFP. These studies demonstrated that prion propagation in HEK cells requires isoform pairing between the infecting prion and the recipient substrate. Interestingly, tau aggregates in AD and CTE, containing both 3R and 4R isoforms, were unable to robustly infect either 3R-or 4R-expressing cells. However, AD and CTE prions were able to replicate in HEK293T cells expressing both 3R and 4R tau. Unexpectedly, increasing the level of 4R isoform expression alone supported the propagation of both AD and CTE prions. These results allowed us to determine the levels of tau prions in AD and CTE brain extracts.argyrophilic grain disease | corticobasal degeneration | Pick's disease | progressive supranuclear palsy | tauopathies

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“…Such a structural polymorphism has been observed in amyloids formed by proteins as varied as lysozyme, insulin, amyloid-␤, ␣-synuclein, tau, ␤ 2 -microglobulin, recombinant mammalian PrP, and the yeast prion protein Sup35 (24,35,(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55). However, the molecular level details giving rise to amyloid strains may vary with the constitutive protein.…”

Section: Discussionmentioning

confidence: 99%

Conformational Stability of Mammalian Prion Protein Amyloid Fibrils Is Dictated by a Packing Polymorphism within the Core Region

Cobb¹,

Apostol²,

Chen³

et al. 2014

Journal of Biological Chemistry

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Background: Prion strains are believed to be enciphered by distinct conformations of misfolded prion protein (PrP). Results: Strains of PrP amyloid with different conformational stabilities were found to have identical ␤-sheet core regions but different steric zipper interfaces. Conclusion: Strain-specific differences in PrP amyloid stability are dictated by a packing polymorphism. Significance: These findings have implications for understanding the structural basis of prion strains.

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Variations in Filament Conformation Dictate Seeding Barrier between Three- and Four-Repeat Tau

Cited by 86 publications

References 48 publications

Brain homogenates from human tauopathies induce tau inclusions in mouse brain

Brain homogenates from human tauopathies induce tau inclusions in mouse brain

Tau prions from Alzheimer’s disease and chronic traumatic encephalopathy patients propagate in cultured cells

Conformational Stability of Mammalian Prion Protein Amyloid Fibrils Is Dictated by a Packing Polymorphism within the Core Region

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