Cellular Models for the Study of Prions

Holmes, Brandon B.; Diamond, Marc I.

doi:10.1101/cshperspect.a024026

Cited by 22 publications

(25 citation statements)

References 49 publications

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“…Therefore, it has been suggested that blocking aggregation may halt disease progression (Bulic et al 2010). Most recently, tau has been found to behave as a prion, passing from cell to cell to propagate its own aggregation (Brunden et al 2008; Clavaguera et al 2015; Stancu et al 2015; see also Holmes and Diamond 2016. )…”

Section: Introduction To Tau Biology and Pathobiologymentioning

confidence: 99%

Interactions between Microtubule-Associated Protein Tau (MAPT) and Small Molecules

Rauch

Olson

Gestwicki

2016

Cold Spring Harb Perspect Med

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Tau aggregation is linked to multiple neurodegenerative disorders that are collectively termed tauopathies. Small molecules are powerful probes of the aggregation process, helping to reveal the key steps and serving as diagnostics and reporters. Moreover, some of these small molecules may have potential as therapeutics. This review details how small molecules and chemical biology have helped to elucidate the mechanisms of tau aggregation and how they are being used to detect and prevent tau aggregation. In addition, we comment on how new insights into tau prions are changing the approach to small molecule discovery.

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Section: Introduction To Tau Biology and Pathobiologymentioning

confidence: 99%

Interactions between Microtubule-Associated Protein Tau (MAPT) and Small Molecules

Rauch

Olson

Gestwicki

2016

Cold Spring Harb Perspect Med

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“…Various modes of transmitting a toxic signal between cells can be envisaged (Brundin et al, 2008, Walsh andSelkoe, 2016). Currently one of the favored mechanisms is based on the "prion-like" spreading of Tau protein, whereby a misfolded and aggregation-prone form of Tau is transferred from a donor to an acceptor cell where it nucleates the conversion of native Tau to a misfolded state and thus causes aggregation (Vaquer-Alicea and Diamond, 2019, Holmes and Diamond, 2017). This is consistent with the fact that Tau is a neuron-speci c protein, and that only neurons develop the abnormal changes of Tau that show up as neuro brillary tangles or neuropil threads, consisting of bundles of paired helical laments (PHF) or straight bers of Tau (SF) (Fitzpatrick et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

FRET-based Tau seeding assay does not represent prion-like templated assembly of Tau filaments

Kaniyappan

Tepper

Biernat

et al. 2020

Preprint

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Tau aggregation into amyloid fibers based on the cross-beta structure is a hallmark of several Tauopathies, including Alzheimer Disease (AD). Trans-cellular propagation of Tau with pathological conformation has been suggested as a key disease mechanism. This is thought to cause the spreading of Tau pathology in AD by templated conversion of naive Tau in recipient cells into a pathological state, followed by assembly of pathological Tau fibers, similar to the mechanism of nucleated polymerization proposed for prion pathogenesis. In cell cultures, the process is often monitored by a FRET assay where the recipient cell expresses the Tau repeat domain (TauRD) with a pro-aggregant mutation, fused to GFP-based FRET pairs. Since the size of the reporter GFP (barrel of ~3nm x 4nm) is ~7 times larger than the β-strand distance (0.47nm), this points to a potential steric clash. Hence, we investigated the influence of the GFP tag on Tau or TauRD aggregation. Using biophysical methods (light scattering, atomic force microscopy (AFM), and scanning-transmission electron microscopy (STEM)), we found that the assembly of TauRD-GFP was severely inhibited and incompatible with that of Alzheimer filaments. These observations argue against the hypothesis that the propagation of Tau pathology in AD is caused by the prion-like templated aggregation of Tau protein, transmitted via cell-to-cell spreading of Tau. Thus, even though the observed local increase of FRET in recipient cells may be a valid hallmark of a pathological reaction, our data argue that it is caused a process distinct from assembly of TauRD filaments.

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“…Expressing a fusion protein consisting of the repeat domain of human tau fused to yellow fluorescent protein (YFP) in human embryonic kidney (HEK) cells enabled tau aggregation to be monitored by the development of microscopic YFP puncta (Holmes et al 2016). Of 29 samples from human tauopathies, 21 induced aggregate formation when incubated with these cells.…”

Section: Bioassays For Non-prp Prionsmentioning

confidence: 99%

Bioassays and Inactivation of Prions

Giles

Woerman

Berry

et al. 2017

Cold Spring Harb Perspect Biol

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The experimental study of prions requires a model for their propagation. However, because prions lack nucleic acids, the simple techniques used to replicate the propagation of bacteria and viruses are not applicable. For much of the history of prion research, time-consuming bioassays in animals were the only option for measuring infectivity. Although cell models and other in vitro tools for the propagation of prions have been developed, they all suffer limitations, and animal bioassays remain the gold standard for measuring infectivity. A wealth of recent data suggests that β-amyloid (Aβ) and tau proteins, which aggregate in Alzheimer’s disease, and α-synuclein, which aggregates in Parkinson’s disease, also become prions. Cell and animal models that recapitulate some of the key features of cell-to-cell spreading of these additional prions have been developed. The unusual resistance of prions to inactivation was an early indication that they represented a different class of infectious agents to bacteria or viruses. Incomplete inactivation of prions has led to medically induced, or iatrogenic, Creutzfeldt–Jakob disease (CJD). Worldwide, the number of elderly individuals who undergo surgery has increased, and due to the unusually long asymptomatic phase of CJD, there are a growing number of cases in which surgical instruments are used on an asymptomatic patient and then reused repeatedly before a CJD diagnosis is confirmed. Recent data suggesting the potential for iatrogenic transmission of Aβ amyloidosis has raised renewed interest in the field of prion inactivation.

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Cellular Models for the Study of Prions

Cited by 22 publications

References 49 publications

Interactions between Microtubule-Associated Protein Tau (MAPT) and Small Molecules

Interactions between Microtubule-Associated Protein Tau (MAPT) and Small Molecules

FRET-based Tau seeding assay does not represent prion-like templated assembly of Tau filaments

Bioassays and Inactivation of Prions

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