Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules

Falcon, Benjamin; Zivanov, Jasenko; Zhang, W; Murzin, Alexey G.; Garringer, Holly J.; Vidal, Rubén; Crowther, R. Anthony; Newell, Kathy L.; Ghetti, Bernardino; Goedert, Michel; Scheres, S.H.W.

doi:10.1038/s41586-019-1026-5

Cited by 554 publications

(687 citation statements)

References 59 publications

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“…Recently, fibrillar aggregates of Tau protein were purified from human postmortem brain from Alzheimer's, Pick's disease, and chronic traumatic encephalopathy patients, showing variations in Tau fibril conformations between diseases (Falcon et al, 2018;Falcon et al, 2019;Fitzpatrick et al, 2017), and these fibrils all differed from the in-vitro generated, heparin-induced tau fibrils . However, to our knowledge, purification of α-Syn fibrils from human brain of Parkinson's disease patients is more challenging.…”

Section: Implications For Fibril Preparation Protocolsmentioning

confidence: 99%

Two new polymorphic structures of alpha-synuclein solved by cryo-electron microscopy

Guerrero-Ferreira

Taylor

Arteni

et al. 2019

Preprint

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Intracellular inclusions rich in alpha-synuclein are a hallmark of several neuropathological diseases including Parkinson's disease (PD). We here report two new polymorphic atomic structures of alpha-synuclein fibrils termed polymorphs 2a and 2b, at 3.0 Å and 3.4 Å resolution, respectively . These polymorphs show a radically different structure compared to previously reported polymorphs. The new structures have a 10 nm fibril diameter and are composed of two protofilaments which interact via intermolecular salt-bridges between amino acids K45, E57 (polymorph 2a) or E46 (polymorph 2b). The non-amyloid component (NAC) region of alpha-synuclein is fully buried by previously non-described interactions with the N-terminus. A hydrophobic cleft, the location of familial PD mutation sites, and the nature of the protofilament interface now invite to formulate hypotheses about fibril formation, growth and stability.

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Section: Implications For Fibril Preparation Protocolsmentioning

confidence: 99%

Two new polymorphic structures of alpha-synuclein solved by cryo-electron microscopy

Guerrero-Ferreira

Taylor

Arteni

et al. 2019

Preprint

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“…[9] 2) It contains several PTM sites ( Figure 1) that have been shown to strongly influence tau aggregation and pathology formation, tau tubulin binding,a nd MT assembly,s tability, and dynamics,a lthough other regions in the protein also influence the dynamics of these processes (Figure 1). 3) Cryo-EM studies of AD [10] and CTE [11] derived tau filaments have revealed that the R3 and R4 repeats constitute the core of the PHFs in the AD brain;similarly,cryo-EM structures derived from narrow pick filaments (NPFs) of Picksd isease brain revealed that the R1, R3, and R4 repeats constitute the core of the NPFs. [12] 4) TheK18 fragments reproduce many of the key features of tau aggregation, exhibit rapid aggregation in vitro, [13] and seed more efficiently in cells [14] than the fulllength tau protein.…”

Section: Introductionmentioning

confidence: 99%

Site‐Specific Hyperphosphorylation Inhibits, Rather than Promotes, Tau Fibrillization, Seeding Capacity, and Its Microtubule Binding

et al. 2020

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The consistent observation of phosphorylated tau in the pathology of Alzheimer's disease has contributed to the emergence of a model where hyperphosphorylation triggers both tau disassociation from microtubules and its subsequent aggregation. Herein, we applied a total chemical synthetic approach to site‐specifically phosphorylate the microtubule binding repeat domain of tau (K18) at single (pS356) or multiple (pS356/pS262 and pS356/pS262/pS258) residues. We show that hyperphosphorylation of K18 inhibits 1) its aggregation in vitro, 2) its seeding activity in cells, 3) its binding to microtubules, and 4) its ability to promote microtubule polymerization. The inhibition increased with increasing the number of phosphorylated sites, with phosphorylation at S262 having the strongest effect. Our results argue against the hyperphosphorylation hypothesis and underscore the importance of revisiting the role of site‐specific hyperphosphorylation in regulating tau functions in health and disease.

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“…Images on brain-derived tau filaments from an ex-professional American football player with chronic traumatic encephalopathy that we recorded on a 300keV Titan Krios microscope showed severe three-and four-fold astigmatism. Correction for these aberrations led to an increase in resolution from 2.7Å to 2.3Å, which allowed visualisation of alternative side chain conformations and of ordered water molecules inside the amyloid filaments (Falcon et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Estimation of High-Order Aberrations and Anisotropic Magnification from Cryo-EM Datasets in RELION-3.1

Zivanov

Nakane

Scheres

2019

Preprint

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We present methods that detect three types of aberrations in single-particle cryo-EM data sets: symmetrical and antisymmetrical optical aberrations and magnification anisotropy. Because our methods only depend on the availability of a preliminary 3D reconstruction from the data, they can be used to correct for these aberrations for any given cryo-EM data set, a posteriori. Using five publicly available data sets, we show that considering these aberrations improves the resolution of the 3D reconstruction when the effects are present. The methods are implemented in version 3.1 of our open-source software package RELION.

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Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules

Cited by 554 publications

References 59 publications

Two new polymorphic structures of alpha-synuclein solved by cryo-electron microscopy

Two new polymorphic structures of alpha-synuclein solved by cryo-electron microscopy

Site‐Specific Hyperphosphorylation Inhibits, Rather than Promotes, Tau Fibrillization, Seeding Capacity, and Its Microtubule Binding

Estimation of High-Order Aberrations and Anisotropic Magnification from Cryo-EM Datasets in RELION-3.1

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