Structural studies of tau protein and Alzheimer paired helical filaments show no evidence for beta-structure.

Schweers, O.; Schönbrunn-Hanebeck, E; Marx, Alexander; Mandelkow, Eckhard

doi:10.1016/s0021-9258(19)51080-8

Cited by 504 publications

(186 citation statements)

References 55 publications

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“…Tau, an intracellular protein involved in promoting microtubule stability and neuronal survival, is the major component of inclusions seen in Alzheimer's disease and other related neurodegenerative tauopathies (Lee et al, 2001). Under normal conditions, tau is a highly soluble protein lacking significant secondary structure (Schweers et al, 1994). However, it undergoes several post-translational modifications resulting in fibrillization into straight-and paired-helical filaments.…”

Section: Introductionmentioning

confidence: 99%

Acetylated tau, a novel pathological signature in Alzheimer's disease and other tauopathies

Irwin

Cohen

Grossman

et al. 2012

Brain

236

230

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The microtubule-binding protein, tau, is the major component of neurofibrillary inclusions characteristic of Alzheimer's disease and related neurodegenerative tauopathies. When tau fibrillizes, it undergoes abnormal post-translational modifications resulting in decreased solubility and altered microtubule-stabilizing properties. Recently, we reported that the abnormal acetylation of tau at lysine residue 280 is a novel, pathological post-translational modification. Here, we performed detailed immunohistochemistry to further examine acetylated-tau expression in Alzheimer's disease and other major tauopathies. Immunohistochemistry using a polyclonal antibody specific for acetylated-tau at lysine 280 was conducted on 30 post-mortem central nervous system regions from patients with Alzheimer's disease (10 patients), corticobasal degeneration (5 patients), and progressive supranuclear palsy (5 patients). Acetylated-tau pathology was compared with the sequential emergence of other tau modifications in the Alzheimer's disease hippocampus using monoclonal antibodies to multiple well-characterized tau epitopes. All cases studied showed significant acetylated-tau pathology in a distribution pattern similar to hyperphosphorylated-tau. Acetylated-tau pathology was largely in intracellular, thioflavin-S-positive tau inclusions in Alzheimer's disease, and also thioflavin-S-negative pathology in corticobasal degeneration and progressive supranuclear palsy. Acetylated-tau was present throughout all stages of Alzheimer's disease pathology, but was more prominently associated with pathological tau epitopes in moderate to severe-stage cases. These temporal and morphological immunohistochemical features suggest acetylation of tau at this epitope is preceded by early modifications, including phosphorylation, and followed by later truncation events and cell death in Alzheimer's disease. Acetylation of tau at lysine 280 is a pathological modification that may contribute to tau-mediated neurodegeneration by both augmenting losses of normal tau properties (reduced solubility and microtubule assembly) as well as toxic gains of function (increased tau fibrillization). Thus, inhibiting tau acetylation could be a disease-modifying target for drug discovery target in tauopathies.

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Section: Introductionmentioning

confidence: 99%

Acetylated tau, a novel pathological signature in Alzheimer's disease and other tauopathies

Irwin

Cohen

Grossman

et al. 2012

Brain

236

230

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“…Scale bar: 100 nm. Schweers et al, 1994 Mass density calculations used the predicted molecular weights determined by sequence analysis; therefore some values listed above will differ from previously published calculations.…”

Section: Discussionmentioning

confidence: 99%

XMAP215 is a long thin molecule that does not increase microtubule stiffness

Cassimeris

Gard

Tran

et al. 2001

Journal of Cell Science

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XMAP215 is a microtubule associated protein that speeds microtubule plus end growth by seven- to tenfold and protects these ends from destabilization by the Kin I kinesin, XKCM1. To understand the mechanisms responsible for these activities, it is necessary to know the structure of XMAP215. By unidirectional shadowing and electron microscopy, XMAP215 appeared as an elongate molecule of 60±18 nm, suggesting that XMAP215 could span up to seven to eight tubulin dimers along a protofilament. Most XMAP215 molecules were straight but a subset were bent suggesting that XMAP215 is flexible. Antibodies to the C terminus labeled one end of XMAP215 with no evidence for XMAP215 dimerization. Incubation of XMAP215 and tubulin at 4°C resulted in assembly of curved protofilaments, which appeared to be incomplete tubulin rings. Measurements from rotary shadowed samples showed that tubulin/XMAP215 partial rings had an average width of 8.8±1.8 nm compared with 5.6±1.1 nm for rings assembled from tubulin dimers alone, suggesting that XMAP215 adds a width of approximately 3.2 nm to the curved tubulin protofilament. XMAP215 did not change the radius of curvature of these partial tubulin rings. Measurements of microtubule flexural rigidity by thermal fluctuations showed that XMAP215 did not change microtubule rigidity. Finally,sequence analysis shows that the N-terminal half of XMAP215 contains four repeats, each composed of multiple HEAT repeats.

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“…Synucleinopathies are a group of neurodegenerative diseases characterized by the aggregation of filamentous α-synuclein into cytosolic inclusion bodies called Lewy bodies (Goedert, 2001). α-synuclein is an intrinsically disordered protein, meaning that it has no defined secondary structure when unbound (Schweers et al, 1994), and it functions at the synapse in vesicle trafficking, plasticity, and inhibition of kinase signalling (Iwata et al, 2001;Chandra et al, 2004;Liu et al, 2004;Chandra et al, 2005;Liu et al, 2007). However, under disease conditions, α-synuclein undergoes a conformational change to a cross β-pleated sheet structure and continues along the path of amyloid fibrillization until ultimately depositing as a Lewy body (Fig.…”

Section: Synucleinopathiesmentioning

confidence: 99%

“…An equally confounding question is the role of SUMOylation in tau pathogenicity. Unbound tau is more likely to be SUMOylated, and this SUMOylated tau leads to an increase in hyperphosphorylation of the protein and protein aggregation (Köpke et al, 1993;Mandelkow et al, 1994). Perhaps SUMOylation of tau is the first step on the road to fibrillization.…”

Section: Taumentioning

confidence: 99%

Ubiquitination and SUMOylation of Amyloid and Amyloid-like Proteins in Health and Disease

Ford¹,

Fioriti²,

Kandel³

2020

Current Issues in Molecular Biology

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Post-translational modifications (PTMs) play important roles in altering the structure and function of proteins. In this article, we focus on ubiquitination and SUMOylation of amyloidogenic proteins. We discuss the functional contributions of PTMs on proteins involved in amyloid-related diseases as well as the aberrant PTM signatures of the disease agents. In addition, we extend our discussion to the nascent field of functional amyloids, a subclass of amyloids that perform physiological functions. Here, we present examples from mammals and yeast to gain insight into physiological regulation of amyloid-like proteins.

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Structural studies of tau protein and Alzheimer paired helical filaments show no evidence for beta-structure.

Cited by 504 publications

References 55 publications

Acetylated tau, a novel pathological signature in Alzheimer's disease and other tauopathies

Acetylated tau, a novel pathological signature in Alzheimer's disease and other tauopathies

XMAP215 is a long thin molecule that does not increase microtubule stiffness

Ubiquitination and SUMOylation of Amyloid and Amyloid-like Proteins in Health and Disease

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