Co-factor-free aggregation of tau into seeding-competent RNA-sequestering amyloid fibrils

Chakraborty, Pijush; Rivière, Gwladys; Liu, Shu; Opakua, Alain Ibáñez de; Dervişoğlu, Rıza; Hebestreit, Alina; Andreas, Loren B.; Vorberg, Ina; Zweckstetter, Markus

doi:10.1038/s41467-021-24362-8

Cited by 46 publications

(45 citation statements)

References 38 publications

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“…In particular, amyloids may bind non-coding RNA [ 79 ]. They also may sequester RNA [ 80 ]. As stress-induced RNA activates amyloidogenesis in vivo [ 81 ], the effect of stress induced sRNA such as DsrA on amyloidogenesis may also occur, such as with DNA [ 45 ], and should be investigated further.…”

Section: Discussionmentioning

confidence: 99%

The Amyloid Region of Hfq Riboregulator Promotes DsrA:rpoS RNAs Annealing

Turbant

Wien

et al. 2021

Biology

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Hfq is a bacterial RNA chaperone which promotes the pairing of small noncoding RNAs to target mRNAs, allowing post-transcriptional regulation. This RNA annealing activity has been attributed for years to the N-terminal region of the protein that forms a toroidal structure with a typical Sm-fold. Nevertheless, many Hfqs, including that of Escherichia coli, have a C-terminal region with unclear functions. Here we use a biophysical approach, Synchrotron Radiation Circular Dichroism (SRCD), to probe the interaction of the E. coli Hfq C-terminal amyloid region with RNA and its effect on RNA annealing. This C-terminal region of Hfq, which has been described to be dispensable for sRNA:mRNA annealing, has an unexpected and significant effect on this activity. The functional consequences of this novel property of the amyloid region of Hfq in relation to physiological stress are discussed.

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Section: Discussionmentioning

confidence: 99%

The Amyloid Region of Hfq Riboregulator Promotes DsrA:rpoS RNAs Annealing

Turbant

Wien

et al. 2021

Biology

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“…We recently overcame this bottleneck and established a co-factor-free assay in which full-length Tau efficiently aggregates into amyloid fibrils. 23…”

Section: Resultsmentioning

confidence: 99%

Hsp multichaperone complex buffers pathologically modified Tau

Moll

Ramirez

Ninov³

et al. 2022

Preprint

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Alzheimer's disease is a neurodegenerative disorder in which misfolding and aggregation of pathologically modified Tau is critical for neuronal dysfunction and degeneration. The two central chaperones Hsp70 and Hsp90 coordinate protein homeostasis, but the nature of the interaction of Tau with the Hsp70/Hsp90 machinery has remained enigmatic. Here we show that Tau is a high-affinity substrate of the human Hsp70/Hsp90 machinery. Complex formation involves extensive intermolecular contacts, blocks Tau aggregation and depends on the Tau aggregation-prone repeat region. The Hsp90 co-chaperone p23 directly binds Tau and stabilizes the multichaperone/substrate complex, whereas the E3 ubiquitin-protein ligase CHIP efficiently disassembles the machinery targeting Tau to proteasomal degradation. Because phosphorylated Tau binds the Hsp70/Hsp90 machinery but is not recognized by Hsp90 alone, the data establish the Hsp70/Hsp90 multichaperone complex as a critical regulator of Tau in neurodegenerative diseases.

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“…Tau is located intracellularly and is subject to posttranslational modifications, including phosphorylation, acetylation, ubiquitylation, and truncation. Tau aggregates into nanofibrils with cofactors ( Goedert et al, 1996 ) and displays typical sigmoidal kinetics of nucleation-dependent protein aggregation ( Chakraborty et al, 2021 ). The smaller aggregates, tau oligomers, are considered more neurotoxic than the neurofibrillary tangle, induce synaptic and mitochondrial dysfunction, and impair memory functions in animal models ( Lasagna-Reeves et al, 2011 ).…”

Section: Tau Imagingmentioning

confidence: 99%

Magnetic Resonance Imaging in Tauopathy Animal Models

2022

Front. Aging Neurosci.

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The microtubule-associated protein tau plays an important role in tauopathic diseases such as Alzheimer’s disease and primary tauopathies such as progressive supranuclear palsy and corticobasal degeneration. Tauopathy animal models, such as transgenic, knock-in mouse and rat models, recapitulating tauopathy have facilitated the understanding of disease mechanisms. Aberrant accumulation of hyperphosphorylated tau contributes to synaptic deficits, neuroinflammation, and neurodegeneration, leading to cognitive impairment in animal models. Recent advances in molecular imaging using positron emission tomography (PET) and magnetic resonance imaging (MRI) have provided valuable insights into the time course of disease pathophysiology in tauopathy animal models. High-field MRI has been applied for in vivo imaging in animal models of tauopathy, including diffusion tensor imaging for white matter integrity, arterial spin labeling for cerebral blood flow, resting-state functional MRI for functional connectivity, volumetric MRI for neurodegeneration, and MR spectroscopy. In addition, MR contrast agents for non-invasive imaging of tau have been developed recently. Many preclinical MRI indicators offer excellent translational value and provide a blueprint for clinical MRI in the brains of patients with tauopathies. In this review, we summarized the recent advances in using MRI to visualize the pathophysiology of tauopathy in small animals. We discussed the outstanding challenges in brain imaging using MRI in small animals and propose a future outlook for visualizing tau-related alterations in the brains of animal models.

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Co-factor-free aggregation of tau into seeding-competent RNA-sequestering amyloid fibrils

Cited by 46 publications

References 38 publications

The Amyloid Region of Hfq Riboregulator Promotes DsrA:rpoS RNAs Annealing

The Amyloid Region of Hfq Riboregulator Promotes DsrA:rpoS RNAs Annealing

Hsp multichaperone complex buffers pathologically modified Tau

Magnetic Resonance Imaging in Tauopathy Animal Models

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