Tau filaments in neurodegenerative diseases

Goedert, Michel

doi:10.1002/1873-3468.13108

Cited by 112 publications

(107 citation statements)

References 66 publications

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“…Hence the 3R/4R tau aggregates in AD have a conformation that is distinct from tau species containing only 3R or 4R tau. This was supported by the recent finding that pTau aggregates in AD, PiD and CBD are characterized by different tau molecular structures with different conformations [21,22,29,76]. Together, these findings suggest that the combination of both 3R and 4R tau isoforms in pTau aggregates in AD, DS with AD, and PART could result in the generation of a common tau conformation, or tau "strain", across these diseases that is then capable of interaction with the same protein co-factors, such as SCRN1.…”

Section: Discussionsupporting

confidence: 57%

O4‐01‐06: Secernin‐1 Is a Novel Phosphorylated Tau Binding Protein That Accumulates in Alzheimer's Disease and Not in Other Tauopathies

Pires

Prelli

Halliday

et al. 2019

Alzheimer's & Dementia

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We recently identified Secernin-1 (SCRN1) as a novel amyloid plaque associated protein using localized proteomics. Immunohistochemistry studies confirmed that SCRN1 was present in plaque-associated dystrophic neurites and also revealed distinct and abundant co-localization with neurofibrillary tangles (NFTs). Little is known about the physiological function of SCRN1 and its role in Alzheimer's disease (AD) and other neurodegenerative diseases has not been studied. Therefore, we performed a comprehensive study of SCRN1 distribution in neurodegenerative diseases. Immunohistochemistry was used to map SCRN1 accumulation throughout the progression of AD in a cohort of 58 patients with a range of NFT pathology (Abundant NFT, n = 21; Moderate NFT, n = 22; Low/No NFT, n = 15), who were clinically diagnosed as having AD, mild cognitive impairment or normal cognition. SCRN1 accumulation was also examined in two cases with both Frontotemporal Lobar Degeneration (FTLD)-Tau and ADrelated neuropathology, cases of Down Syndrome (DS) with AD (n = 5), one case of hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) and other non-AD tauopathies including: primary age-related tauopathy (PART, [n = 5]), Corticobasal Degeneration (CBD, [n = 5]), Progressive Supranuclear Palsy (PSP, [n = 5]) and Pick's disease (PiD, [n = 4]). Immunohistochemistry showed that SCRN1 was a neuronal protein that abundantly accumulated in NFTs and plaque-associated dystrophic neurites throughout the progression of AD. Quantification of SCRN1 immunohistochemistry confirmed that SCRN1 preferentially accumulated in NFTs in comparison to surrounding non-tangle containing neurons at both early and late stages of AD. Similar results were observed in DS with AD and PART. However, SCRN1 did not co-localize with phosphorylated tau inclusions in CBD, PSP or PiD. Coimmunoprecipitation revealed that SCRN1 interacted with phosphorylated tau in human AD brain tissue. Together, these results suggest that SCRN1 is uniquely associated with tau pathology in AD, DS and PART. As such, SCRN1 has potential as a novel therapeutic target and could serve as a useful biomarker to distinguish AD from other tauopathies.

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Section: Discussionsupporting

confidence: 57%

O4‐01‐06: Secernin‐1 Is a Novel Phosphorylated Tau Binding Protein That Accumulates in Alzheimer's Disease and Not in Other Tauopathies

Pires

Prelli

Halliday

et al. 2019

Alzheimer's & Dementia

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“…The microtubule-associated protein tau is implicated in the pathophysiology of a range of neurodegenerative diseases, but also has a role as a non-specific biomarker of neuronal damage. In a misfolded and phosphorylated state it is a principal component of diseaseassociated protein aggregates in a range of so-called "tauopathies" including Alzheimer's disease, corticobasal degeneration, progressive supranuclear palsy and some forms of frontotemporal dementia (49). Although not a classical pathological hallmark of prion disease, it has been shown that phosphorylated tau deposits are a prominent autopsy finding in some inherited prion diseases (50).…”

Section: Taumentioning

confidence: 99%

Review: Fluid biomarkers in the human prion diseases

Thompson

Mead

2019

Molecular and Cellular Neuroscience

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The human prion diseases are a diverse set of often rapidly progressive neurodegenerative conditions associated with abnormal forms of the prion protein. We review work to establish diagnostic biomarkers and assays that might fill other important roles, particularly those that could assist the planning and interpretation of clinical trials. The field now benefits from highly sensitive and specific diagnostic biomarkers using cerebrospinal fluid: detecting by-products of rapid neurodegeneration or specific functional properties of abnormal prion protein, with the second generation real time quaking induced conversion (RT-QuIC) assay being particularly promising. Blood has been a more challenging analyte, but has now also yielded valuable biomarkers. Blood-based assays have been developed with the potential to screen for variant Creutzfeldt-Jakob disease, although it remains uncertain whether these will ever be used in practice. The very rapid neurodegeneration of prion disease results in strong signals from surrogate protein markers in the blood that reflect neuronal, axonal, synaptic or glial pathology in the brain: notably the tau and neurofilament light chain proteins. We discuss early evidence that such tests, applied alongside robust diagnostic biomarkers, may have potential to add value as clinical trial outcome measures, predictors of future disease course (including for asymptomatic individuals at high risk of prion disease), and as rapidly accessible and sensitive markers to aid early diagnosis.

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“…Tau protein is abundantly expressed in the nervous systems, especially in nerve cell axons, and intrinsically disordered with a low content of secondary structures [21]. Tau has six isoforms depending on patterns of alternative splicing of the exons 2, 3, and 10.…”

Section: Progresses In Investigation Of Tau Amyloidsmentioning

confidence: 99%

Mechanisms of strain diversity of disease-associated in-register parallel β-sheet amyloids and implications about prion strains

Taguchi

Otaki

Nishida

2018

Preprint

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18The mechanism of strain diversity of prions still remains unsolved, because the investigation of inheritance and 19 diversification of the protein-based pathogenic information demands identification of the detailed structures of abnormal 20 isoform of prion protein (PrP Sc ), while it is difficult to purify for analysis without affecting the infectious nature. On the other 21 hand, the similar prion-like properties are recognized also in other disease-associated in-register parallel β -sheet amyloids 22 including Tau and α -synuclein (αSyn) amyloids. Investigations into structures of those amyloids by solid-state nuclear 23 magnetic resonance spectroscopy and cryo-electron microscopy recently made remarkable advances, because of their 24 relatively small sizes and lack of post-translational modifications. We review the advances on those pathogenic amyloids, 25 particularly Tau and α Syn, and discuss their implications about strain diversity mechanisms of prion/PrP Sc from the 26 viewpoint that PrP Sc is an in-register parallel β -sheet amyloid. We also present our recent data of molecular dynamics 27 simulations of α Syn amyloid, which suggest significance of compatibility between β -sheet propensities of the substrate and 28 local structures of the template for stability of the amyloid structures. Detailed structures of the α Syn and Tau amyloids are 29 good surrogate models of pathogenic amyloids including PrP Sc to elucidate not only the strain diversity but also their 30 pathogenic mechanisms. 31 32 33Strain diversity is one of the most mysterious feature of prions. The strain-specific traits of prions are enciphered in 34 the structures of the abnormal isoform prion protein (PrP Sc ), and they are stably inherited over generations solely by 35 passaging the exact structures of the PrP Sc through template-directed refolding of the normal isoform prion protein (PrP C ), 36 where the template PrP Sc imprint the structural details onto the substrate PrP C . Moreover, the strain-specific pathogenic 37 information encoded in the conformation of the PrP Sc is reproducibly "translated" into the strain-specific clinicopathological 38 traits in the manifested diseases [1] [2]. This view is widely accepted as the protein-only hypothesis but detailed 39 mechanisms, e.g., specifically what structures of PrP Sc encodes the pathogenic information and how the information is 40 translated, remain a challenge to the current biology. Investigations of the storage, inheritance and diversification of the 41 protein-based pathogenic information demand identification of the structure-phenotype correlations, but it is very difficult 42 because detailed structures of the entire PrP Sc is not available yet due to its incompatibility with high-resolution structural 43 analyses, i.e., X-ray crystallography or nuclear magnetic resonance spectrometry (NMR). The incompatibility is attributable 44 to difficulty in purification without losing infectivity [3], difficulty in recapitulating bona fide prion...

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Tau filaments in neurodegenerative diseases

Cited by 112 publications

References 66 publications

O4‐01‐06: Secernin‐1 Is a Novel Phosphorylated Tau Binding Protein That Accumulates in Alzheimer's Disease and Not in Other Tauopathies

O4‐01‐06: Secernin‐1 Is a Novel Phosphorylated Tau Binding Protein That Accumulates in Alzheimer's Disease and Not in Other Tauopathies

Review: Fluid biomarkers in the human prion diseases

Mechanisms of strain diversity of disease-associated in-register parallel β-sheet amyloids and implications about prion strains

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