scholarly journals Molecular Processing of Tau Protein in Progressive Supranuclear Palsy: Neuronal and Glial Degeneration

2021 ◽  
Vol 79 (4) ◽  
pp. 1517-1531
Author(s):  
Alejandra Martínez-Maldonado ◽  
Miguel Ángel Ontiveros-Torres ◽  
Charles R. Harrington ◽  
José Francisco Montiel-Sosa ◽  
Raúl García-Tapia Prandiz ◽  
...  
Keyword(s):  
Progressive Supranuclear Palsy ◽  
Glial Cells ◽  
Conformational Changes ◽  
Tau Protein ◽  
Paired Helical Filaments ◽  
Phosphorylated Tau ◽  
Clinical Heterogeneity ◽  
Post Translational Modifications ◽  
Binding Domains ◽  
Tau Isoforms

Background: Alzheimer’s disease (AD) and progressive supranuclear palsy (PSP) are examples of neurodegenerative diseases, characterized by abnormal tau inclusions, that are called tauopathies. AD is characterized by highly insoluble paired helical filaments (PHFs) composed of tau with abnormal post-translational modifications. PSP is a neurodegenerative disease with pathological and clinical heterogeneity. There are six tau isoforms expressed in the adult human brain, with repeated microtubule-binding domains of three (3R) or four (4R) repeats. In AD, the 4R:3R ratio is 1:1. In PSP, the 4R isoform predominates. The lesions in PSP brains contain phosphorylated tau aggregates in both neurons and glial cells. Objective: Our objective was to evaluate and compare the processing of pathological tau in PSP and AD. Methods: Double and triple immunofluorescent labeling with antibodies to specific post-translational tau modifications (phosphorylation, truncation, and conformational changes) and thiazin red (TR) staining were carried out and analyzed by confocal microscopy. Results: Our results showed that PSP was characterized by phosphorylated tau in neurofibrillary tangles (NFTs) and glial cells. Tau truncated at either Glu391 or Asp421 was not observed. Extracellular NFTs (eNFTs) and glial cells in PSP exhibited a strong affinity for TR in the absence of intact or phosphorylated tau. Conclusion: Phosphorylated tau was as abundant in PSP as in AD. The development of eNFTs from both glial cells and neuronal bodies suggests that truncated tau species, different from those observed in AD, could be present in PSP. Additional studies on truncated tau within PSP lesions could improve our understanding of the pathological processing of tau and help identify a discriminatory biomarker for AD and PSP.

scholarly journals Tau protein is phosphorylated by cyclic AMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II within its microtubule-binding domains at Ser-262 and Ser-356

1996 ◽  
Vol 316 (2) ◽  
pp. 655-660 ◽  
Author(s):  
Joel M. LITERSKY ◽  
Gail V. W. JOHNSON ◽  
Ross JAKES ◽  
Michel GOEDERT ◽  
Michael LEE ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cyclic Amp ◽  
Tau Protein ◽  
Paired Helical Filaments ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Protein Kinase ◽  
Calcium Calmodulin Dependent ◽  
Binding Domains ◽  
Protein Kinase Ii ◽  
Dependent Protein

Phosphorylation of tau protein at Ser-262 has been shown to diminish its ability to bind to taxol-stabilized microtubules. The paired helical filaments (PHFs) found in Alzheimer's disease brain are composed of PHF-tau, which is hyperphosphorylated at multiple sites including Ser-262. However, protein kinase(s) able to phosphorylate this site are still under investigation. In this study, the ability of cyclic AMP-dependent protein kinase (cAMP-PK) and calcium/calmodulin-dependent protein kinase II (CaMKII) to phosphorylate tau at Ser-262, as well as Ser-356, is demonstrated by use of a monoclonal antibody (12E8) which has been shown to recognize tau when these sites are phosphorylated. Cleavage of cAMP-PK-phosphorylated tau at cysteine residues by 2-nitro-5-thiocyanobenzoic acid, which cuts the protein into essentially two fragments and separates Ser-262 from Ser-356, revealed that cAMP-PK phosphorylates both Ser-262 and Ser-356. In addition, phosphorylation with cAMP-PK or CaMKII of recombinant tau in which Ser-262, Ser-356 or both had been mutated to alanines, clearly demonstrated that cAMP-PK and CaMKII were able to phosphorylate both sites. Mitogen-activated protein kinase or protein kinase C did not phosphorylate tau at Ser-262 and/or Ser-356. Finally, evidence is presented that phosphorylation of both these sites occurs in cultured nerve cells under certain conditions, indicating their potential physiological relevance.

scholarly journals A68 proteins in Alzheimer's disease are composed of several tau isoforms in a phosphorylated state which affects their electrophoretic mobilities

1991 ◽  
Vol 279 (3) ◽  
pp. 831-836 ◽  
Author(s):  
J P Brion ◽  
D P Hanger ◽  
A M Couck ◽  
B H Anderton
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Alkaline Phosphatase ◽  
Synthetic Peptides ◽  
Paired Helical Filaments ◽  
Phosphorylated Tau ◽  
Electrophoretic Mobilities ◽  
Sds Page ◽  
Tau Isoforms ◽  
Antibodies To Synthetic Peptides

The tau-immunoreactive A68 polypeptides found in brains from patients with Alzheimer's disease have been studied by Western blotting using (1) antibodies to synthetic peptides corresponding to sequences that span the complete human tau molecule, and (2) antibodies specific for inserts 1 and 2 found towards the N-terminus of some tau isoforms. The three major A68 polypeptides were labelled by all of the antibodies to sequences common to all tau isoforms, but the faster-migrating A68 polypeptides was not labelled by either of the two antibodies specific for inserts 1 and 2. Treatment with alkaline phosphatase of non-solubilized A68 did not change its electrophoretic mobility on SDS/PAGE under the conditions described here. However, A68 that was solubilized before treating it with alkaline phosphatase was found to move faster on SDS/PAGE than untreated A68, to a position similar to that of normal tau. We also confirmed that A68 preparations contain numerous paired helical filaments (PHF). These PHF were labelled by all anti-tau antibodies, including insert-specific antibodies. Our results further support the notion that PHF contain abnormally phosphorylated tau in an aggregated state, and indicate that these abnormally phosphorylated tau forms are composed of several tau isoforms and that the full length of the tau molecule is present in these polypeptides.

Targeting Tau Hyperphosphorylation via Kinase Inhibition: Strategy to Address Alzheimer's Disease

2020 ◽  
Vol 20 (12) ◽  
pp. 1059-1073 ◽  
Author(s):  
Ahmad Abu Turab Naqvi ◽  
Gulam Mustafa Hasan ◽  
Md. Imtaiyaz Hassan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Glycogen Synthase ◽  
Paired Helical Filaments ◽  
Tau Hyperphosphorylation ◽  
Microtubule Stabilization ◽  
Extracellular Signal

Microtubule-associated protein tau is involved in the tubulin binding leading to microtubule stabilization in neuronal cells which is essential for stabilization of neuron cytoskeleton. The regulation of tau activity is accommodated by several kinases which phosphorylate tau protein on specific sites. In pathological conditions, abnormal activity of tau kinases such as glycogen synthase kinase-3 β (GSK3β), cyclin-dependent kinase 5 (CDK5), c-Jun N-terminal kinases (JNKs), extracellular signal-regulated kinase 1 and 2 (ERK1/2) and microtubule affinity regulating kinase (MARK) lead to tau hyperphosphorylation. Hyperphosphorylation of tau protein leads to aggregation of tau into paired helical filaments like structures which are major constituents of neurofibrillary tangles, a hallmark of Alzheimer’s disease. In this review, we discuss various tau protein kinases and their association with tau hyperphosphorylation. We also discuss various strategies and the advancements made in the area of Alzheimer's disease drug development by designing effective and specific inhibitors for such kinases using traditional in vitro/in vivo methods and state of the art in silico techniques.

scholarly journals A structural framework for unidirectional transport by a bacterial ABC exporter

2020 ◽  
Vol 117 (32) ◽  
pp. 19228-19236
Author(s):  
Chengcheng Fan ◽  
Jens T. Kaiser ◽  
Douglas C. Rees
Keyword(s):  
Conformational Changes ◽  
Iron Homeostasis ◽  
Atp Hydrolysis ◽  
Transmembrane Helix ◽  
Reverse Direction ◽  
Conformational States ◽  
X Ray Crystallography ◽  
Binding Domains ◽  
Structural Framework ◽  
Glutathione Derivatives

The ATP-binding cassette (ABC) transporter of mitochondria (Atm1) mediates iron homeostasis in eukaryotes, while the prokaryotic homolog fromNovosphingobium aromaticivorans(NaAtm1) can export glutathione derivatives and confer protection against heavy-metal toxicity. To establish the structural framework underlying theNaAtm1 transport mechanism, we determined eight structures by X-ray crystallography and single-particle cryo-electron microscopy in distinct conformational states, stabilized by individual disulfide crosslinks and nucleotides. AsNaAtm1 progresses through the transport cycle, conformational changes in transmembrane helix 6 (TM6) alter the glutathione-binding site and the associated substrate-binding cavity. Significantly, kinking of TM6 in the post-ATP hydrolysis state stabilized by MgADPVO4eliminates this cavity, precluding uptake of glutathione derivatives. The presence of this cavity during the transition from the inward-facing to outward-facing conformational states, and its absence in the reverse direction, thereby provide an elegant and conceptually simple mechanism for enforcing the export directionality of transport byNaAtm1. One of the disulfide crosslinkedNaAtm1 variants characterized in this work retains significant glutathione transport activity, suggesting that ATP hydrolysis and substrate transport by Atm1 may involve a limited set of conformational states with minimal separation of the nucleotide-binding domains in the inward-facing conformation.

scholarly journals Effects of resveratrol and morin on insoluble tau in tau transgenic mice

2018 ◽  
Vol 9 (1) ◽  
pp. 54-60 ◽  
Author(s):  
Kwun Chung Yu ◽  
Ping Kwan ◽  
Stanley K.K. Cheung ◽  
Amy Ho ◽  
Larry Baum
Keyword(s):  
Transgenic Mice ◽  
Motor Function ◽  
Tau Protein ◽  
Late Stage ◽  
Animal Studies ◽  
Paired Helical Filaments ◽  
Hyperphosphorylated Tau ◽  
Total Tau ◽  
Tau Aggregation ◽  
Do So

Abstract Tauopathies are neurodegenerative diseases, including Alzheimer’s disease (AD) and frontotemporal dementia (FTD), in which tau protein aggregates within neurons. An effective treatment is lacking and is urgently needed. We evaluated two structurally similar natural compounds, morin and resveratrol, for treating tauopathy in JNPL3 P301L mutant human tau overexpressing mice. Rotarod tests were performed to determine effects on motor function. After treatment from age 11 to 14 months, brains of 26 mice were collected to quantify aggregated hyperphosphorylated tau by Thioflavin T and immunohistochemistry (IHC) and to quantify total tau (HT7 antibody) and hyperphosphorylated tau (AT8 antibody) in homogenates and a fraction enriched for paired helical filaments. Resveratrol reduced the level of total hyperphosphorylated tau in IHC sections (p=0.036), and morin exhibited a tendency to do so (p=0.29), while the two drugs tended to increase the proportion of solubilizable tau that was hyperphosphorylated, as detected in blots. Neither resveratrol nor morin affected motor function. One explanation of these results is that the drugs might interrupt a late stage in tau aggregation, after small aggregates have formed but before further aggregation has occurred. Further animal studies would be informative to explore the possible efficacy of morin or resveratrol for treating tauopathies.

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