Amplification of Tau Fibrils from Minute Quantities of Seeds

Meyer, Virginia; Dinkel, Paul D.; Hager, Emily R; Margittai, Martin

doi:10.1021/bi501050g

Cited by 62 publications

(55 citation statements)

References 44 publications

(74 reference statements)

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“…32). In vitro studies on disease-associated proteins such as prion and tau showed that fragmentation of long fibrils, usually achieved by sonication, is critical for efficient seeded amplification (33,34). Moreover, it has been further demonstrated that only short tau fibrils, but not long fibrils, can be internalized and transported by neurons (35).…”

Section: Discussionmentioning

confidence: 99%

The Dynamics and Turnover of Tau Aggregates in Cultured Cells

Guo

Buist

Soares

et al. 2016

Journal of Biological Chemistry

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Filamentous tau aggregates, the hallmark lesions of Alzheimer disease (AD), play key roles in neurodegeneration. Activation of protein degradation systems has been proposed to be a potential strategy for removing pathological tau, but it remains unclear how effectively tau aggregates can be degraded by these systems. By applying our previously established cellular model system of AD-like tau aggregate induction using preformed tau fibrils, we demonstrate that tau aggregates induced in cells with regulated expression of full-length mutant tau can be gradually cleared when soluble tau expression is suppressed. This clearance is at least partially mediated by the autophagy-lysosome pathway, although both the ubiquitin-proteasome system and the autophagy-lysosome pathway are deficient in handling large tau aggregates. Importantly, residual tau aggregates left after the clearance phase leads to a rapid reinstatement of robust tau pathology once soluble tau expression is turned on again. Moreover, we succeeded in generating monoclonal cells persistently carrying tau aggregates without obvious cytotoxicity. Live imaging of GFP-tagged tau aggregates showed that tau inclusions are dynamic structures constantly undergoing "fission" and "fusion," which facilitate stable propagation of tau pathology in dividing cells. These findings provide a greater understanding of cell-to-cell transmission of tau aggregates in dividing cells and possibly neurons.Filamentous aggregates made up of hyperphosphorylated tau protein are the defining pathological feature of numerous neurodegenerative diseases, such as Alzheimer disease, corticobasal degeneration, progressive supranuclear palsy, and Pick disease, which are collectively termed tauopathies (reviewed by Ref. 1). Physiologically, tau is a highly soluble microtubule-associated protein important for the assembly and stability of microtubules (2, 3). Insoluble, aggregated tau that is hyperphosphorylated and conformationally altered not only loses its physiological role of binding microtubules, but can also physically interfere with normal functioning of other cellular components (reviewed by Ref. 4). Strong correlations of the distribution and severity of tau pathology with clinical phenotypes of tauopathy patients (5-7) support the key contribution of aggregated tau to neuronal dysfunction and degeneration in these diseases, although some studies suggest pre-fibrillar tau species, such as oligomers, could be equally, if not more toxic than mature tau fibrils (8 -11).One obvious strategy to treat tauopathies is to remove intracellular tau aggregates either by promoting the disassembly of tau fibrils or by activating cellular degradation machineries to clear these toxic entities. A recent study demonstrated that it is possible to reverse mature tau inclusions together with associated neuronal deficits by suppressing soluble tau expression in a mouse model with inducible expression of tau, but the exact mechanism of tau pathology clearance was not explored (12). There are two primary pro...

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Section: Discussionmentioning

confidence: 99%

The Dynamics and Turnover of Tau Aggregates in Cultured Cells

Guo

Buist

Soares

et al. 2016

Journal of Biological Chemistry

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“…In each case, one single or very few specific host protein(s) or peptides like Tau, a-synuclein, superoxide dismutase 1 (SOD1), Tar DNA-binding protein 43 (TDP-43), prion protein (PrP) or b-amyloid peptide (Ab) misfolds from a soluble native conformation into a harmful aggregated state, rich in beta sheets [2][3][4][5][6][7][8][9][10][11][12]. Amplification of misfolding through seeded/nucleated polymerization leads to not fully defined toxic species and neuronal destruction.…”

Section: Introductionmentioning

confidence: 99%

Efficient inhibition of infectious prions multiplication and release by targeting the exosomal pathway

Vilette

Laulagnier

Huor

et al. 2015

Cell. Mol. Life Sci.

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Exosomes are secreted membrane vesicles of endosomal origin present in biological fluids. Exosomes may serve as shuttles for amyloidogenic proteins, notably infectious prions, and may participate in their spreading in vivo. To explore the significance of the exosome pathway on prion infectivity and release, we investigated the role of the endosomal sorting complex required for transport (ESCRT) machinery and the need for ceramide, both involved in exosome biogenesis. Silencing of HRS-ESCRT-0 subunit drastically impairs the formation of cellular infectious prion due to an altered trafficking of cholesterol. Depletion of Tsg101-ESCRT-I subunit or impairment of the production of ceramide significantly strongly decreases infectious prion release. Together, our data reveal that ESCRT-dependent and -independent pathways can concomitantly regulate the exosomal secretion of infectious prion, showing that both pathways operate for the exosomal trafficking of a particular cargo. These data open up a new avenue to regulate prion release and propagation.

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“…While seeding aggregation with AD brainderived PHFs has been reported in vitro for recombinant Tau (22,23), as well as in vivo (24)(25)(26), it still does not answer whether phosphorylation can drive the initial nucleation of fibers.…”

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confidence: 99%

Identification of the Tau phosphorylation pattern that drives its aggregation

Despres

Byrne

et al. 2017

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

184

190

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Determining the functional relationship between Tau phosphorylation and aggregation has proven a challenge owing to the multiple potential phosphorylation sites and their clustering in the Tau sequence. We use here in vitro kinase assays combined with NMR spectroscopy as an analytical tool to generate well-characterized phosphorylated Tau samples and show that the combined phosphorylation at the Ser202/Thr205/Ser208 sites, together with absence of phosphorylation at the Ser262 site, yields a Tau sample that readily forms fibers, as observed by thioflavin T fluorescence and electron microscopy. On the basis of conformational analysis of synthetic phosphorylated peptides, we show that aggregation of the samples correlates with destabilization of the turn-like structure defined by phosphorylation of Ser202/Thr205.

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Amplification of Tau Fibrils from Minute Quantities of Seeds

Cited by 62 publications

References 44 publications

The Dynamics and Turnover of Tau Aggregates in Cultured Cells

The Dynamics and Turnover of Tau Aggregates in Cultured Cells

Efficient inhibition of infectious prions multiplication and release by targeting the exosomal pathway

Identification of the Tau phosphorylation pattern that drives its aggregation

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