scholarly journals From genetics to pathology: tau and a–synuclein assemblies in neurodegenerative diseases

2001 ◽  
Vol 356 (1406) ◽  
pp. 213-227 ◽  
Author(s):  
Michel Goedert ◽  
Maria Grazia Spillantini ◽  
Louise C. Serpell ◽  
John Berriman ◽  
Michael J. Smith ◽  
...  
Keyword(s):  
Human Brain ◽  
Neurodegenerative Diseases ◽  
Frontotemporal Dementia ◽  
Glial Cells ◽  
Tau Protein ◽  
Nerve Cells ◽  
Degenerative Diseases ◽  
Protein Tau ◽  
Microtubule Associated Protein Tau ◽  
Filamentous Inclusions

The most common degenerative diseases of the human brain are characterized by the presence of abnormal filamentous inclusions in affected nerve cells and glial cells. These diseases can be grouped into two classes, based on the identity of the major proteinaceous components of the filamentous assemblies. The filaments are made of either the microtubule–associated protein tau or the protein α–synuclein. Importantly, the discovery of mutations in the tau gene in familial forms of frontotemporal dementia and of mutations in the α–synuclein gene in familial forms of Parkinson's disease has established that dysfunction of tau protein and α–synuclein can cause neurodegeneration.

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 Invited review: Frontotemporal dementia caused by microtubule‐associated protein tau gene ( MAPT ) mutations: a chameleon for neuropathology and neuroimaging

2015 ◽  
Vol 41 (1) ◽  
pp. 24-46 ◽  
Author(s):  
Bernardino Ghetti ◽  
Adrian L. Oblak ◽  
Bradley F. Boeve ◽  
Keith A. Johnson ◽  
Bradford C. Dickerson ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Protein Tau ◽  
Microtubule Associated Protein Tau

scholarly journals DrosophilaModels of Tauopathies: What Have We Learned?

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Marc Gistelinck ◽  
Jean-Charles Lambert ◽  
Patrick Callaerts ◽  
Bart Dermaut ◽  
Pierre Dourlen
Keyword(s):  
Frontotemporal Dementia ◽  
High Throughput ◽  
Neurodegenerative Disorders ◽  
Genetic Model ◽  
Model Organism ◽  
Molecular Pathways ◽  
Protein Tau ◽  
Microtubule Associated Protein Tau ◽  
The Past ◽  
Genome Wide

Aggregates of the microtubule-associated protein Tau are neuropathological hallmark lesions in Alzheimer's disease (AD) and related primary tauopathies. In addition, Tau is genetically implicated in a number of human neurodegenerative disorders including frontotemporal dementia (FTD) and Parkinson's disease (PD). The exact mechanism by which Tau exerts its neurotoxicity is incompletely understood. Here, we give an overview of how studies using the genetic model organismDrosophilaover the past decade have contributed to the molecular understanding of Tau neurotoxicity. We compare the different available readouts for Tau neurotoxicity in flies and review the molecular pathways in which Tau has been implicated. Finally, we emphasize that the integration of genome-wide approaches in human or mice with high-throughput genetic validation inDrosophilais a fruitful approach.

scholarly journals Microglia become hypofunctional and release metalloproteases and tau seeds after phagocytosing live neurons with P301S tau aggregates

2021 ◽  
Author(s):  
Maria Grazia Spillantini ◽  
Jack H Brelstaff ◽  
Matthew Mason ◽  
Taxiarchis Katsinelos ◽  
William A McEwan ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Neurodegenerative Diseases ◽  
Matrix Remodeling ◽  
Matrix Metalloprotease ◽  
Protein Tau ◽  
Microtubule Associated Protein Tau ◽  
Senescent Phenotype ◽  
Human Brains ◽  
Tau Aggregate

The microtubule-associated protein tau aggregates in multiple neurodegenerative diseases, causing inflammation and changing the inflammatory signature of microglia by unknown mechanisms. We have shown that microglia phagocytose live neurons containing tau aggregates cultured from P301S tau transgenic mice due to neuronal tau aggregate-induced exposure of the 'eat me' signal phosphatidylserine. Here we show that after phagocytosis, microglia become hypophagocytic while releasing seed-competent insoluble tau aggregates. These microglia activate acidic β-galactosidase, and release senescence-associated cytokines and matrix remodeling enzymes alongside tau, indicating a senescent phenotype. In particular, the marked NFκB-induced activation of matrix metalloprotease 3 (MMP3/stromelysin1) was replicated in the brains of P301S mutant tau transgenic mice, and in human brains from tauopathy patients. These data show that microglia that have been activated to ingest live neurons with tau aggregates behave hormetically, becoming hypofunctional while acting as vectors of tau aggregate spreading.

Current Concepts in the Classification and Diagnosis of Frontotemporal Lobar Degenerations: A Practical Approach

2014 ◽  
Vol 138 (1) ◽  
pp. 132-138 ◽  
Author(s):  
Zdenek Rohan ◽  
Radoslav Matej
Keyword(s):  
Frontotemporal Dementia ◽  
Glial Cells ◽  
Tau Protein ◽  
Frontotemporal Lobar Degeneration ◽  
Dna Binding Protein ◽  
Nonfluent Aphasia ◽  
Fused In Sarcoma ◽  
Clinical Syndromes ◽  
Pathologic Processes ◽  
Progressive Nonfluent Aphasia

Frontotemporal lobar degenerations are clinically, genetically, and molecularly heterogeneous diseases characterized by mainly frontal and temporal atrophy and affecting behavioral, language, cognitive, and motor functions. The term frontotemporal dementia incorporates 3 distinct clinical syndromes seen in frontotemporal degenerations: behavioral variant of frontotemporal dementia, progressive nonfluent aphasia, and semantic dementia. Progressive supranuclear palsy syndrome, corticobasal syndrome, and motor neuron disease syndrome are also associated with frontotemporal lobar degenerations. The neuropathologic hallmark of frontotemporal lobar degenerations is accumulation of abnormal proteins in the cytoplasm and nuclei of neurons and glial cells. Proteins involved in pathologic processes that represent the basis for frontotemporal lobar degeneration classification are tau protein, transactive response DNA-binding protein of 43 kDa, and “fused in sarcoma” protein. The aim of this review is to provide a summary of practical approaches for neuropathologic diagnostics of the rapidly evolving classifications of frontotemporal lobar degenerations.

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