scholarly journals Recent High-Resolution Structures of Amyloids Involved in Neurodegenerative Diseases

2021 ◽  
Vol 13 ◽  
Author(s):  
Rodrigo Diaz-Espinoza
Keyword(s):  
Electron Microscopy ◽  
High Resolution ◽  
Neurodegenerative Diseases ◽  
Neurodegenerative Disorders ◽  
Solid State Nmr ◽  
Molecular Level ◽  
Molecular Targets ◽  
Protein Tau ◽  
Isolation Methods

Amyloids are highly ordered aggregates composed of proteins or peptides. They are involved in several pathologies, including hallmark neurodegenerative disorders such as Alzheimer’s (AD) and Parkinson’s (PD). Individuals affected by these diseases accumulate in their brains amyloids inclusions composed of misfolded forms of a peptide (Aβ) and a protein (Tau) in AD and α-synuclein protein (α-Sn) in PD. Tau and α-Sn aggregates are also present in other neurodegenerative diseases. The insoluble nature and heterogeneity of amyloids have hampered their study at the molecular level. However, the use of solid state NMR and Cryogenic-electron microscopy along with fine-tuned modulation of the aggregation in vitro and improved isolation methods of brain-derived amyloids has allowed the elucidation of these elusive conformations at high resolution. In this work, we review the latest progress on the recent amyloid structures reported for Aβ, Tau, and α-Sn. The two-fold symmetry emerges as a convergent feature in the tridimensional arrangement of the protofilaments in the fibrillary structure of these pathological amyloids, with many of them exhibiting a Greek-key topology as part of their overall architecture. These specific features can serve as novel guides to seek potential molecular targets in drug design efforts.

scholarly journals Heparin-induced tau filaments are polymorphic and differ from those in Alzheimer’s and Pick’s diseases

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Wenjuan Zhang ◽  
Benjamin Falcon ◽  
Alexey G Murzin ◽  
Juan Fan ◽  
R Anthony Crowther ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Neurodegenerative Diseases ◽  
Protein Tau ◽  
Microtubule Associated Protein Tau ◽  
The Third ◽  
In Vitro Assembly ◽  
Immuno Electron Microscopy ◽  
Structural Versatility ◽  
Filamentous Inclusions

Assembly of microtubule-associated protein tau into filamentous inclusions underlies a range of neurodegenerative diseases. Tau filaments adopt different conformations in Alzheimer’s and Pick’s diseases. Here, we used cryo- and immuno- electron microscopy to characterise filaments that were assembled from recombinant full-length human tau with four (2N4R) or three (2N3R) microtubule-binding repeats in the presence of heparin. 2N4R tau assembles into multiple types of filaments, and the structures of three types reveal similar ‘kinked hairpin’ folds, in which the second and third repeats pack against each other. 2N3R tau filaments are structurally homogeneous, and adopt a dimeric core, where the third repeats of two tau molecules pack in a parallel manner. The heparin-induced tau filaments differ from those of Alzheimer’s or Pick’s disease, which have larger cores with different repeat compositions. Our results illustrate the structural versatility of amyloid filaments, and raise questions about the relevance of in vitro assembly.

scholarly journals Heparin-induced tau filaments are polymorphic and differ from those in Alzheimer’s and Pick’s diseases

2018 ◽  
Author(s):  
Wenjuan Zhang ◽  
Benjamin Falcon ◽  
Alexey G. Murzin ◽  
Juan Fan ◽  
R. Anthony Crowther ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Neurodegenerative Diseases ◽  
Microtubule Binding ◽  
Protein Tau ◽  
Microtubule Associated Protein Tau ◽  
The Third ◽  
Negative Stain ◽  
Different Types ◽  
Filamentous Inclusions

AbstractThe assembly of microtubule-associated protein tau into abundant filamentous inclusions underlies a range of neurodegenerative diseases. The finding that tau filaments adopt different conformations in Alzheimer’s and Pick’s diseases raises the question of what kinds of structures of tau filaments form in vitro. Here, we used electron cryo-microscopy (cryo-EM) and negative-stain immuno-gold electron microscopy (immuno-EM) to characterise filaments that were assembled from recombinant full-length human tau with four (2N4R) or three (2N3R) microtubule-binding repeats in the presence of heparin. 4R tau assembles into at least four different types of filaments. Cryo-EM structures of three types of 4R filaments reveal similar “kinked hairpin” folds, in which the second and third repeats pack against each other. 3R tau filaments are structurally homogeneous, and adopt a dimeric core, where the third repeats of two tau molecules pack against each other in a parallel, yet asymmetric, manner. None of the heparin-induced tau filaments resemble those of Alzheimer’s or Pick’s disease, which have larger cores with different repeat compositions. Our results indicate that tau filaments are structurally versatile, and raise questions about the relevance of in vitro assembled amyloids.

scholarly journals Prion Diseases: A Unique Transmissible Agent or a Model for Neurodegenerative Diseases?

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 207
Author(s):  
Diane L. Ritchie ◽  
Marcelo A. Barria
Keyword(s):  
Public Health ◽  
Neurodegenerative Diseases ◽  
Prion Protein ◽  
Neurodegenerative Disorders ◽  
Prion Diseases ◽  
Experimental Models ◽  
Misfolded Proteins ◽  
Current Evidence

The accumulation and propagation in the brain of misfolded proteins is a pathological hallmark shared by many neurodegenerative diseases such as Alzheimer’s disease (Aβ and tau), Parkinson’s disease (α-synuclein), and prion disease (prion protein). Currently, there is no epidemiological evidence to suggest that neurodegenerative disorders are infectious, apart from prion diseases. However, there is an increasing body of evidence from experimental models to suggest that other pathogenic proteins such as Aβ and tau can propagate in vivo and in vitro in a prion-like mechanism, inducing the formation of misfolded protein aggregates such as amyloid plaques and neurofibrillary tangles. Such similarities have raised concerns that misfolded proteins, other than the prion protein, could potentially transmit from person-to-person as rare events after lengthy incubation periods. Such concerns have been heightened following a number of recent reports of the possible inadvertent transmission of Aβ pathology via medical and surgical procedures. This review will provide a historical perspective on the unique transmissible nature of prion diseases, examining their impact on public health and the ongoing concerns raised by this rare group of disorders. Additionally, this review will provide an insight into current evidence supporting the potential transmissibility of other pathogenic proteins associated with more common neurodegenerative disorders and the potential implications for public health.

scholarly journals Phase separation of proSAAS into spheres results in core sequestration of TDP-43216-414 aggregates

2020 ◽  
Author(s):  
Juan R. Peinado ◽  
Kriti Chaplot ◽  
Timothy S. Jarvela ◽  
Edward Barbieri ◽  
James Shorter ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Phase Separation ◽  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
Model System ◽  
Chaperone Activity ◽  
Chaperone Proteins ◽  
Cytotoxic Effects ◽  
Vital Functions

SUMMARYChaperone proteins perform vital functions in the maintenance of cellular proteostasis and play important roles during the development of neurodegenerative diseases involving protein aggregation. We have previously reported that a secreted neuronal chaperone known as proSAAS exhibits potent chaperone activity in vitro against protein aggregation and blocks the cytotoxic effects of amyloid and α-synuclein oligomers. Here we report that overexpression of proSAAS generates dense, membraneless 2 μm spheres which can increase by fusion up to 4 μM during expression within the cytoplasm. The presence of dense proSAAS spheres was confirmed using electron microscopy. ProSAAS spheres selectively sequestered GFP-TDP-43216-414 within their cores, resulting in cellular redistribution and retardation of degradation. ProSAAS expression was protective against TDP-43 cytotoxicity in a yeast model system. Aggregate sequestration via proSAAS encapsulation may provide protection from cell-to-cell transmission of aggregates and explain the as-yet unclear mechanism underlying the cytoprotective chaperone action of proSAAS.

scholarly journals NEURODEGENERATIVE DISEASES AND TAU: PATHOLOGICAL EVENTS AND MOLECULAR TARGETS

2012 ◽  
Author(s):  
Pierfausto Seneci
Keyword(s):  
Neurodegenerative Diseases ◽  
Molecular Targets ◽  
Negative Regulator ◽  
Structural Domains ◽  
Post Translational Modifications ◽  
Protein Tau ◽  
Neuronal Protein ◽  
Positive Regulator ◽  
Trans Isomerization ◽  
Biochemical Abnormalities

The neuronal protein tau, and the related neurodegenerative diseases named tauopathies, are thoroughly described here. Tau is characterized in terms of its disorganized structure, of its isoforms, and of its structural domains. Tau mutations, and their consequences on the functions of tau (detachment from microtubules, aggregation into soluble oligomers and insoluble aggregates), are mentioned to introduce a set of ≈30 tauopathies. The pattern of post-translational modifications of tau is described, to explain its impact – when disregulated – on the folding and mislocalization of tau, followed by its aggregation. In details, tau hyper-phosphorylation (negative regulator, to be inhibited), N-Acetylglucosamine glycosylation and pT231-P232 cis-trans isomerization (positive regulator, to be stimulated) are described in terms of their connection to tau biochemical abnormalities, and of their exploitation as tauopathy-directed molecular targets.

scholarly journals Nuclear Fragility in Radiation-Induced Senescence: Blebs and Tubes Visualized by 3D Electron Microscopy

Cells ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 273
Author(s):  
Benjamin M. Freyter ◽  
Mutaz A. Abd Al-razaq ◽  
Anna Isermann ◽  
Anne Dietz ◽  
Omid Azimzadeh ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Dna Damage ◽  
High Resolution ◽  
Imaging Techniques ◽  
Morphological Organization ◽  
3D Electron Microscopy ◽  
Radiation Induced ◽  
3D Electron ◽  
Vitro Model

Irreparable DNA damage following ionizing radiation (IR) triggers prolonged DNA damage response and induces premature senescence. Cellular senescence is a permanent state of cell-cycle arrest characterized by chromatin restructuring, altered nuclear morphology and acquisition of secretory phenotype, which contributes to senescence-related inflammation. However, the mechanistic connections for radiation-induced DNA damage that trigger these senescence-associated hallmarks are poorly understood. In our in vitro model of radiation-induced senescence, mass spectrometry-based proteomics was combined with high-resolution imaging techniques to investigate the interrelations between altered chromatin compaction, nuclear envelope destabilization and nucleo-cytoplasmic chromatin blebbing. Our findings confirm the general pathophysiology of the senescence-response, with disruption of nuclear lamin organization leading to extensive chromatin restructuring and destabilization of the nuclear membrane with release of chromatin fragments into the cytosol, thereby activating cGAS-STING-dependent interferon signaling. By serial block-face scanning electron microscopy (SBF-SEM) whole-cell datasets were acquired to investigate the morphological organization of senescent fibroblasts. High-resolution 3-dimensional (3D) reconstruction of the complex nuclear shape allows us to precisely visualize the segregation of nuclear blebs from the main nucleus and their fusion with lysosomes. By multi-view 3D electron microscopy, we identified nanotubular channels formed in lamin-perturbed nuclei of senescent fibroblasts; the potential role of these nucleo-cytoplasmic nanotubes for expulsion of damaged chromatin has to be examined.

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