Tau gene mutations and neurodegeneration

2001 ◽  
Vol 67 ◽  
pp. 59-71 ◽  
Author(s):  
Michel Goedert ◽  
Maria Grazia Spillantini
Keyword(s):  
Tau Protein ◽  
Donor Site ◽  
Gene Mutations ◽  
Corticobasal Degeneration ◽  
Chromosome 17 ◽  
Splice Donor Site ◽  
Coding Region ◽  
Tau Pathology ◽  
Tau Isoforms ◽  
Exon 10

Abundant neurofibrillary lesions made of the microtubule-associated protein tau constitute a defining neuropathological characteristic of Alzheimer's disease. Filamentous tau protein deposits are also the defining neuropathological characteristic of other neurodegenerative diseases, many of which are frontotemporal dementias or movement disorders, such as Pick's disease, progressive supranuclear palsy and corticobasal degeneration. It is well established that the distribution of tau pathology correlates with the presence of symptoms of disease. However, until recently, there was no genetic evidence linking dysfunction of tau protein to neurodegeneration and dementia. This has now changed with the discovery of close to 20 mutations in the tau gene in frontotemporal dementia with Parkinsonism linked to chromosome 17. All cases with tau mutations examined to date have shown an abundant filamentous tau pathology in brain cells. Pathological heterogeneity is determined to a large extent by the location of mutations in tau. Known mutations are either coding region or intronic mutations located close to the splice-donor site of the intron downstream of exon 10. Most coding region mutations produce a reduced ability of tau to interact with microtubules. Several of these mutations also promote sulphated glycosaminoglycan-induced assembly of tau into filaments. Intronic mutations and some coding region mutations produce increased splicing in of exon 10, resulting in an overexpression of four-repeat tau isoforms. Thus a normal ratio of three-repeat to four-repeat tau isoforms is essential for preventing the development of tau pathology. The new work has shown that dysfunction of tau protein can cause neurodegeneration and dementia.

scholarly journals Tauopathies: A Distinct Class of Neurodegenerative Diseases

2007 ◽  
Vol 10 (2) ◽  
pp. 3-14 ◽  
Author(s):  
M Ozansoy ◽  
A Başak
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurofibrillary Tangles ◽  
Neuronal Loss ◽  
Corticobasal Degeneration ◽  
Chromosome 17 ◽  
Cell Degeneration ◽  
Distinct Class ◽  
Postencephalitic Parkinsonism ◽  
Tau Isoforms ◽  
Niemann Pick

Tauopathies: A Distinct Class of Neurodegenerative DiseasesNeurodegenerative diseases are characterized by neuronal loss and intraneuronal accumulation of fibrillary materials, of which, neurofibrillary tangles (NFT) are the most common. Neurofibrillary tangles also occur in normal aging and contain the hyperphosphorylated microtubule-associated protein tau. A detailed presentation is made of the molecular bases of Alzheimer's disease (AD), postencephalitic parkinsonism, amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) of Guam, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick's disease, frontotemporal dementia (FTD), Down's syndrome, myotonic dystrophy (DM) and Niemann-Pick Type C (NPC) disease, which are considered to be common tauopathies. The unique human tau gene extends over 100 kb of the long arm of chromosome 17 and contains 16 exons. The human brain contains six tau isoforms that contain from 352 to 441 amino acids. To date, 34 pathogenic tau mutations have been described among 101 families affected by FTD with parkinsonism linked to chromosome 17 (FTDP-17). These mutations may involve alternative splicing of exon 10 that lead to changes in the proportion of 4-repeat- and 3-repeat-tau isoforms, or may modify tau interactions with microtubules. Tau aggregates differ in degree of phosphorylation and in content of tau isoforms. Five classes of tauopathies have been defined depending on the type of tau aggregates. The key event in tauopathies is the disorganization of the cytoskeleton, which is based on mutations/polymorphisms in the tau gene and lead to nerve cell degeneration. In this review, tauopathies as a distinct class of neurodegenerative diseases are discussed with emphasis on their molecular pathology and genetics.

scholarly journals Role of molecular polymorphism in defining tau filament structures in neurodegenerative diseases

2021 ◽  
Author(s):  
Xinyu Xiang ◽  
Tamta Arakhamia ◽  
Yari Carlomagno ◽  
Shikhar Dhingra ◽  
Manon Thierry ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Tau Protein ◽  
Molecular Level ◽  
Corticobasal Degeneration ◽  
Molecular Polymorphism ◽  
Cofactor Binding ◽  
Tau Isoforms ◽  
The Brain ◽  
Disease Specific

Misfolding and aggregation of tau protein is implicated in many neurodegenerative diseases that are typified by the presence of large, filamentous tau inclusions. The aggregation of tau in human brain is disease-specific with characteristic filaments defining the neuropathology. An understanding of how identical tau isoforms aggregate into disparate filament morphologies in phenotypically distinct tau-related diseases remains elusive. Here, we determine the structure of a brain-derived twisted tau filament in progressive supranuclear palsy and compare it to a dissimilar tau fold found in corticobasal degeneration. While the tau filament core in both diseases is comprised of residues 274 to 380, molecular-level polymorphism exists. Potential origins of the molecular polymorphism, such as noncovalent cofactor binding, are identified and predicted to modulate tau filament structures in the brain.

Mpl Genotype and Phenotype Correlations in the Chronic Myeloproliferative Disorders: Relationship of Mpl Mutations, JAK2V617F Status and Mpl Protein Expression.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3615-3615
Author(s):  
Donna M. Williams ◽  
Ann H. Kim ◽  
Ophelia Rogers ◽  
Jerry L. Spivak ◽  
Alison R. Moliterno
Keyword(s):  
Protein Expression ◽  
Donor Site ◽  
Myeloproliferative Disorders ◽  
Extramedullary Hematopoiesis ◽  
Reciprocal Relationship ◽  
Cell Surface Expression ◽  
Splice Donor Site ◽  
Base Substitution ◽  
Chronic Myeloproliferative Disorders ◽  
Exon 10

Abstract The chronic myeloproliferative disorders (MPD), polycythemia vera (PV), essential thrombocytosis (ET) and idiopathic myelofibrosis (IMF), are linked by a common genetic lesion, JAK2V617F, and abnormalities of the thrombopoietin receptor, Mpl. JAK2 is an obligate Mpl chaperone and is responsible for its cell surface expression. We observed a reciprocal relationship between neutrophil JAK2V617F allele percentage and platelet Mpl expression in JAK2V617F-positive PV, IMF and ET patients. However, severely impaired platelet Mpl expression was also present in the majority of JAK2V617F-negative PV and IMF patients, with the most severe reductions in IMF. We previously identified a constitutional variation in the Mpl gene in the distal N-terminal domain (K39N) associated with thrombocytosis, and an Mpl splice variant involving the same region that was increased in PV and IMF patients compared to controls. Given the association of Mpl genetic lesions and protein expression abnormalities in the MPD, we hypothesized that other lesions in Mpl may be present in the MPD. To test this, we sequenced all of the exons, the flanking intervening sequences and the 5′-proximal untranslated region of the Mpl gene in 1 ET, 3 PV and 4 IMF patients, all of whom were JAK2V617F-negative and all of whom had markedly reduced (<5%) platelet Mpl protein. In one IMF patient, we identified a two base substitution at nucleotide 1543 of the Mpl gene which results in a tryptophan to lysine substitution at amino acid 515 (W515K); the wild-type sequence was not identified from either peripheral blood CD34+ cells or neutrophils isolated from this patient. The patient developed IMF at the age of 26, and had the disease 23 years before succumbing to complications of extensive extramedullary hematopoiesis and anemia. In a second male patient, we identified a heterozygous nucleotide transition in the intervening sequence distal to exon 10 close to the splice donor site; the mutation was also detected in buccal cell DNA. This patient developed IMF at age 35 and has had the disease for 31 years characterized by anemia and extramedullary hematopoiesis. To test whether this or other lesions in exon 10 of the Mpl gene were present, we directly sequenced exon 10 in 9 patients with JAK2V617F-negative PV, 21 with JAK2V617F-negative IMF, and 13 with JAK2V617F-positive IMF. Neither these nor other lesions in exon 10 were identified in these 43 MPD patients; no other unreported SNPs were identified either. We did not identify the recently described MplW515L reported as present in 4/44 JAK2V617F-negative IMF patients (PLoS Med.2006;3:e270) in our 21 JAK2V617F-negative IMF patients. These data indicate that, in contrast to other cytokine receptors, genetic and epigenetic variations of Mpl have unique roles in the pathogenesis of the chronic MPD. We conclude that significant disruptions of Mpl, whether acquired or constitutional, at the genomic level as described above or at the proteomic level as we have previously described, associate with a chronic MPD characterized by significant extramedullary hematopoiesis.

scholarly journals Specific Profile of Tau Isoforms in Argyrophylic Grain Disease

2013 ◽  
Vol 7 ◽  
pp. JEN.S12202 ◽  
Author(s):  
Alberto Rábano ◽  
Raquel Cuadros ◽  
Miguel Calero ◽  
Félix Hernández ◽  
Jesús Avila
Keyword(s):  
Progressive Supranuclear Palsy ◽  
Corticobasal Degeneration ◽  
Hyperphosphorylated Tau ◽  
Tau Pathology ◽  
Intermediate Group ◽  
Tau Isoforms ◽  
Group 3 ◽  
Tau Isoform ◽  
Intracellular Aggregates ◽  
Specific Profile

Argyrophylic grain disease (AGD) is a neurodegenerative condition that has been classified among the sporadic tauopathies. Entities in this group present intracellular aggregates of hyperphosphorylated tau, giving rise to characteristic neuronal and glial inclusions. In different tauopathies, the proportion of several tau isoforms present in the aggregates shows specific patterns. AGD has been tentatively classified in the 4R group (predominance of 4R tau isoforms) together with progressive supranuclear palsy and corticobasal degeneration. Pick's disease is included in the 3R group (predominance of 3R isoforms), whereas tau pathology of Alzheimer's disease represents and intermediate group (3 or 4 repeats [3R plus 4R, respectively] isoforms). In this work, we have analyzed tau present in aggregates isolated from brain samples of patients with argyrophylic grain disease. Our results indicate that the main tau isoform present in aggregates obtained from patients with AGD is a hyperphosphorylated isoform containing exons 2 and 10 but lacking exon 3.

scholarly journals Human tau pathology transmits glial tau aggregates in the absence of neuronal tau

2019 ◽  
Vol 217 (2) ◽  
Author(s):  
Sneha Narasimhan ◽  
Lakshmi Changolkar ◽  
Dawn M. Riddle ◽  
Alexandra Kats ◽  
Anna Stieber ◽  
...  
Keyword(s):  
White Matter ◽  
Mouse Model ◽  
Mouse Brain ◽  
Tau Protein ◽  
Corticobasal Degeneration ◽  
Cell Loss ◽  
Tau Pathology ◽  
Abnormal Accumulation ◽  
Nontg Mouse ◽  
Functional Consequences

Tauopathies are characterized by abnormal accumulation of tau protein in neurons and glia. In Alzheimer’s disease (AD), tau aggregates in neurons, while in corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), tau also aggregates in astrocytes and oligodendrocytes. We previously demonstrated that human CBD and PSP tauopathy lysates (CBD-tau and PSP-tau) contain distinct tau strains that propagate neuronal and glial tau aggregates in nontransgenic (nonTg) mouse brain. Yet the mechanism of glial tau transmission is unknown. Here, we developed a novel mouse model to knock down tau in neurons to test for glial tau transmission. While oligodendroglial tau pathology propagated across the mouse brain in the absence of neuronal tau pathology, astrocytic tau pathology did not. Oligodendroglial tau aggregates propagated along white matter tracts independently of neuronal axons, and resulted in oligodendrocyte cell loss. Thus, glial tau pathology has significant functional consequences independent of neuronal tau pathology.

scholarly journals In vitro amplification of pathogenic tau conserves disease-specific bioactive characteristics

2021 ◽  
Author(s):  
Hong Xu ◽  
Mia O’Reilly ◽  
Garrett S. Gibbons ◽  
Lakshmi Changolkar ◽  
Jennifer D. McBride ◽  
...  
Keyword(s):  
Tau Protein ◽  
Biological Activities ◽  
Corticobasal Degeneration ◽  
Tau Pathology ◽  
Protein Tau ◽  
Beta Sheet Structure ◽  
Sheet Structure ◽  
Strain Dependent ◽  
Disease Specific

AbstractThe microtubule-associated protein tau (tau) forms hyperphosphorylated aggregates in the brains of tauopathy patients that can be pathologically and biochemically defined as distinct tau strains. Recent studies show that these tau strains exhibit strain-specific biological activities, also referred to as pathogenicities, in the tau spreading models. Currently, the specific pathogenicity of human-derived tau strains cannot be fully recapitulated by synthetic tau preformed fibrils (pffs), which are generated from recombinant tau protein. Reproducing disease-relevant tau pathology in cell and animal models necessitates the use of human brain-derived tau seeds. However, the availability of human-derived tau is extremely limited. Generation of tau variants that can mimic the pathogenicity of human-derived tau seeds would significantly extend the scale of experimental design within the field of tauopathy research. Previous studies have demonstrated that in vitro seeding reactions can amplify the beta-sheet structure of tau protein from a minute quantity of human-derived tau. However, whether the strain-specific pathogenicities of the original, human-derived tau seeds are conserved in the amplified tau strains has yet to be experimentally validated. Here, we used biochemically enriched brain-derived tau seeds from Alzheimer’s disease (AD), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) patient brains with a modified seeding protocol to template the recruitment of recombinant 2N4R (T40) tau in vitro. We quantitatively interrogated efficacy of the amplification reactions and the pathogenic fidelity of the amplified material to the original tau seeds using recently developed sporadic tau spreading models. Our data suggest that different tau strains can be faithfully amplified in vitro from tau isolated from different tauopathy brains and that the amplified tau variants retain their strain-dependent pathogenic characteristics.

Tau alternative splicing in familial and sporadic tauopathies

2012 ◽  
Vol 40 (4) ◽  
pp. 677-680 ◽  
Author(s):  
Michael Niblock ◽  
Jean-Marc Gallo
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Alternative Splicing ◽  
Chromosome 17 ◽  
Binding Motif ◽  
Neuronal Viability ◽  
Protein Tau ◽  
Rna Analysis ◽  
Tau Isoforms ◽  
Exon 10

Six tau isoforms differing in their affinity for microtubules are produced by alternative splicing from the MAPT (microtubule-associated protein tau) gene in adult human brain. Several MAPT mutations causing the familial tauopathy, FTDP-17 (frontotemporal dementia with parkinsonism linked to chromosome 17), affect alternative splicing of exon 10, encoding a microtubule-binding motif. Advanced RNA analysis methods have suggested that levels of exon 10-containing MAPT mRNA are elevated in Alzheimer's disease. Furthermore, the MAPT H1 haplotype, associated with Alzheimer's disease, promotes exon 10 inclusion in MAPT mRNA. Thus an accurate regulation of tau alternative splicing is critical for the maintenance of neuronal viability, and its alteration might be a contributing factor to Alzheimer's disease. Tau alternative splicing could represent a target for therapeutic intervention to delay the progression of pathology in familial as well as sporadic tauopathies.

scholarly journals Insoluble Tau From Human FTDP-17 Cases Exhibit Unique Transmission Properties In Vivo

2020 ◽  
Vol 79 (9) ◽  
pp. 941-949
Author(s):  
Sarah A Weitzman ◽  
Sneha Narasimhan ◽  
Zhuohao He ◽  
Lakshmi Changolkar ◽  
Jennifer D McBride ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Tau Protein ◽  
Protein A ◽  
Chromosome 17 ◽  
Intracellular Accumulation ◽  
Tau Pathology ◽  
Clinical Presentations ◽  
Hyperphosphorylated Tau Protein ◽  
Human Brains

Abstract One hallmark of neurodegenerative diseases is the intracellular accumulation of hyperphosphorylated tau protein, a neuronal microtubule-associated protein, into structures known as neurofibrillary tangles. Tauopathies are heterogeneous neurodegenerative diseases caused by the misfolding of the tau protein. It has been previously shown that the tau protein can spread from cell to cell in a prion-like manner. Tauopathies can be sporadic or familial, with the identification of pathogenic mutations in the microtubule-associated protein tau gene on chromosome 17 in the familial cases. Different frontotemporal dementia with parkinsonism-17 (FTDP-17) cases are associated with varying clinical presentations and types of neuropathology. We previously demonstrated that insoluble tau extracted from sporadic tauopathy human brains contain distinct tau strains, which underlie the heterogeneity of these diseases. Furthermore, these tau strains seeded tau aggregates that resemble human tau neuropathology in nontransgenic and 6hTau mice in vivo. Here, we show insoluble tau from human brains of FTDP-17 cases transmit different patterns of neuronal and glial tau pathology in vivo, similar to the sporadic tauopathies. This suggests that each of these tau mutations has unique properties that underlie the heterogeneity of FTDP-17 cases.

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