scholarly journals Non-Canonical Roles of Tau and Their Contribution to Synaptic Dysfunction

2021 ◽  
Vol 22 (18) ◽  
pp. 10145
Author(s):  
Giacomo Siano ◽  
Chiara Falcicchia ◽  
Nicola Origlia ◽  
Antonino Cattaneo ◽  
Cristina Di Primio
Keyword(s):  
Tau Protein ◽  
Neurodegenerative Disorders ◽  
Neuronal Degeneration ◽  
Synaptic Dysfunction ◽  
Cell Soma ◽  
Post Translational Modifications ◽  
Synaptic Homeostasis ◽  
Wide Range ◽  
And Function ◽  
Tau Aggregation

Tau plays a central role in a group of neurodegenerative disorders collectively named tauopathies. Despite the wide range of diverse symptoms at the onset and during the progression of the pathology, all tauopathies share two common hallmarks, namely the misfolding and aggregation of Tau protein and progressive synaptic dysfunctions. Tau aggregation correlates with cognitive decline and behavioural impairment. The mechanistic link between Tau misfolding and the synaptic dysfunction is still unknown, but this correlation is well established in the human brain and also in tauopathy mouse models. At the onset of the pathology, Tau undergoes post-translational modifications (PTMs) inducing the detachment from the cytoskeleton and its release in the cytoplasm as a soluble monomer. In this condition, the physiological enrichment in the axon is definitely disrupted, resulting in Tau relocalization in the cell soma and in dendrites. Subsequently, Tau aggregates into toxic oligomers and amyloidogenic forms that disrupt synaptic homeostasis and function, resulting in neuronal degeneration. The involvement of Tau in synaptic transmission alteration in tauopathies has been extensively reviewed. Here, we will focus on non-canonical Tau functions mediating synapse dysfunction.

scholarly journals Pharmacological Modulators of Tau Aggregation and Spreading

2020 ◽  
Vol 10 (11) ◽  
pp. 858
Author(s):  
Antonio Dominguez-Meijide ◽  
Eftychia Vasili ◽  
Tiago Fleming Outeiro
Keyword(s):  
Tau Protein ◽  
Neurodegenerative Disorders ◽  
Molecular Mechanisms ◽  
Mechanisms Of Action ◽  
Tau Aggregation ◽  
The Brain ◽  
Pharmacological Modulators

Tauopathies are neurodegenerative disorders characterized by the deposition of aggregates composed of abnormal tau protein in the brain. Additionally, misfolded forms of tau can propagate from cell to cell and throughout the brain. This process is thought to lead to the templated misfolding of the native forms of tau, and thereby, to the formation of newer toxic aggregates, thereby propagating the disease. Therefore, modulation of the processes that lead to tau aggregation and spreading is of utmost importance in the fight against tauopathies. In recent years, several molecules have been developed for the modulation of tau aggregation and spreading. In this review, we discuss the processes of tau aggregation and spreading and highlight selected chemicals developed for the modulation of these processes, their usefulness, and putative mechanisms of action. Ultimately, a stronger understanding of the molecular mechanisms involved, and the properties of the substances developed to modulate them, will lead to the development of safer and better strategies for the treatment of tauopathies.

scholarly journals Lysine methylation is an endogenous post-translational modification of tau protein in human brain and a modulator of aggregation propensity

2014 ◽  
Vol 462 (1) ◽  
pp. 77-88 ◽  
Author(s):  
Kristen E. Funk ◽  
Stefani N. Thomas ◽  
Kelsey N. Schafer ◽  
Grace L. Cooper ◽  
Zhongping Liao ◽  
...  
Keyword(s):  
Human Brain ◽  
Tau Protein ◽  
Protein Function ◽  
Lysine Methylation ◽  
Post Translational Modification ◽  
Post Translational Modifications ◽  
Aggregation Propensity ◽  
Normal Human ◽  
Tau Aggregation

Diverse post-translational modifications regulate tau protein function and misfolding. In the present study we identified lysine methylation as a tau post-translational modification in normal human brain, and found it depressed tau aggregation propensity when modelled in vitro.

scholarly journals The Large-Conductance, Calcium-Activated Potassium Channel: A Big Key Regulator of Cell Physiology

2021 ◽  
Vol 12 ◽  
Author(s):  
Maria Sancho ◽  
Barry D. Kyle
Keyword(s):  
Bk Channels ◽  
Bk Channel ◽  
Channel Structure ◽  
Cell Physiology ◽  
Ongoing Research ◽  
Post Translational Modifications ◽  
Wide Range ◽  
And Function ◽  
Calcium Activated Potassium Channel ◽  
Silver Bullet

Large-conductance Ca2+-activated K+ channels facilitate the efflux of K+ ions from a variety of cells and tissues following channel activation. It is now recognized that BK channels undergo a wide range of pre- and post-translational modifications that can dramatically alter their properties and function. This has downstream consequences in affecting cell and tissue excitability, and therefore, function. While finding the “silver bullet” in terms of clinical therapy has remained elusive, ongoing research is providing an impressive range of viable candidate proteins and mechanisms that associate with and modulate BK channel activity, respectively. Here, we provide the hallmarks of BK channel structure and function generally, and discuss important milestones in the efforts to further elucidate the diverse properties of BK channels in its many forms.

The physiology and pathology of microtubule-associated protein tau

2014 ◽  
Vol 56 ◽  
pp. 111-123 ◽  
Author(s):  
Jian-Zhi Wang ◽  
Xinya Gao ◽  
Zhi-Hao Wang
Keyword(s):  
Neurodegenerative Disorders ◽  
Single Gene ◽  
Polyacrylamide Gel Electrophoresis ◽  
Gene Mutations ◽  
Tau Proteins ◽  
Microtubule Assembly ◽  
Research Progress ◽  
Post Translational Modification ◽  
Post Translational Modifications ◽  
Wide Range

Tau belongs to the family of microtubule-associated proteins predominantly expressed in neurons where they play an important role in promoting microtubule assembly and stabilizing microtubules. In addition, tau proteins interact with other cytoskeletal elements to allow spacing between microtubules. Recent studies have shown that tau is also actively involved in regulating cell viability and activity. Translated from a single gene located on chromosome 17q21, six isoforms of tau are produced by alternative splicing in adult human brain. Due to multiple post-translational modifications, heterogeneous tau species with a wide range of apparent molecular masses have been observed by denaturing polyacrylamide-gel electrophoresis. Since tau gene mutations and abnormal post-translational modifications have been detected in over 20 neurodegenerative disorders, namely the tauopathies, tau has gained widespread attention as a target protein in Alzheimer's disease and other neurodegenerative disorders. In the present chapter, research progress regarding physiology and pathology of tau is reviewed, particularly in terms of the role of post-translational modification.

Proteomics and Neurodegenerative Disorders: Advancements in the Diagnostic Analysis

2020 ◽  
Vol 21 (12) ◽  
pp. 1174-1183
Author(s):  
Nidhi Puranik ◽  
Dhananjay Yadav ◽  
Shiv Kumar Yadav ◽  
Vishal K. Chavda ◽  
Jun-O Jin
Keyword(s):  
Early Diagnosis ◽  
Neurodegenerative Disorders ◽  
Clinical Symptoms ◽  
The Body ◽  
Post Translational Modifications ◽  
Protein Protein Interaction ◽  
Protein Levels ◽  
Significant Difference ◽  
Neuronal Proteins ◽  
And Function

: Changes in protein structure and function, alteration in protein-protein interaction, and significant difference in protein concentration inside the body could play an important role in indicating the pathological evidence of abnormalities before the development of clinical symptoms and act as a critical detection and diagnostic tool commonly known as biomarkers. Biomarkers play important roles in the diagnosis of various chronic diseases, including cancer. Neurodegenerative disorders, including Parkinson's, Alzheimer's, Huntington's, prion, and multiple sclerosis, are well characterized by neuronal deterioration, resulting in precise modifications of neuronal proteins. Nowadays, the diagnosis of neurological disorders is based on proteins or biomarkers. These biomarkers may be found in the cerebrospinal fluid, blood, serum, plasma, saliva, or urine sample. Early diagnosis is urgently needed to prevent further damage. For early diagnosis, identifying the changes in novel protein levels and their functions under the disease conditions is necessary. These can be used as specific proteomic biomarkers for diseases, and they can be possibly identified using neuroproteomics. Neuroproteomics is an emerging tool to corroborate disease-associated protein profiles. It also gives an idea about how these proteins interact with other proteins and undergo post-translational modifications. Neuroproteomics is based on bioinformatics, which provides functional characteristics and advances in technology such as mass spectroscopy, and can help in the discovery of various disease-specific biomarkers. This review gives a complete idea about the types of biomarkers, sources of biomarkers, and techniques involved in the discovery of biomarkers for early diagnosis of neurodegenerative diseases.

scholarly journals Visualization of Tau–Tubulin Interaction in a Living Cell Using Bifluorescence Complementation Technique

2018 ◽  
Vol 19 (10) ◽  
pp. 2978 ◽  
Author(s):  
Seulgi Shin ◽  
Sungsu Lim ◽  
Hyeanjeong Jeong ◽  
Li Kwan ◽  
Yun Kim
Keyword(s):  
Neurodegenerative Disorders ◽  
Living Cell ◽  
Neuronal Degeneration ◽  
Cell Model ◽  
Chemical Stimulation ◽  
Aggregation Process ◽  
Phosphorylated Tau ◽  
Tau Pathology ◽  
A Cell ◽  
Tau Aggregation

Tau is a neuron-specific microtubule-binding protein that stabilizes microtubules. It is generally thought that highly phosphorylated tau dissociates from microtubules and becomes insoluble aggregates, leading to neuronal degeneration. Due to the implication of tau aggregation in neurodegenerative disorders, including Alzheimer’s disease, great efforts have been made to identify the tau aggregation process. However, tau interaction with tubulin during the aggregation process remains largely unknown. To scrutinize the tau-tubulin interaction, we generated a cell model that enables visualization of the tau-tubulin interaction in a living cell using the Bifluorescence Complementation (BiFC) Technique. Upon diverse chemical stimulation that induced tau pathology, tau-tubulin BiFC cells showed significantly increased levels of BiFC fluorescence, indicating that tau aggregates together with tubulin. Our results suggest that tubulin should be considered as a key component in the tau aggregation process.

scholarly journals Novel Protein Kinase Inhibitors Related to Tau Pathology Modulate Tau Protein-Self Interaction Using a Luciferase Complementation Assay

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2335 ◽  
Author(s):  
Max Holzer ◽  
Nico Schade ◽  
Ansgar Opitz ◽  
Isabel Hilbrich ◽  
Jens Stieler ◽  
...  
Keyword(s):  
Protein Kinases ◽  
Tau Protein ◽  
Kinase Inhibitors ◽  
Neuronal Degeneration ◽  
Protein Kinase Inhibitors ◽  
Tau Hyperphosphorylation ◽  
Hyperphosphorylated Tau Protein ◽  
Viable Approach ◽  
Gsk 3Β ◽  
Tau Aggregation

The current number of drugs available for the treatment of Alzheimer’s disease (AD) is strongly limited and their benefit for therapy is given only in the early state of the disease. An effective therapy should affect those processes which mainly contribute to the neuronal decay. There have been many approaches for a reduction of toxic Aβ peptides which mostly failed to halt cognitive deterioration in patients. The formation of neurofibrillary tangles (NFT) and its precursor tau oligomers have been suggested as main cause of neuronal degeneration because of a direct correlation of their density to the degree of dementia. Reducing of tau aggregation may be a viable approach for the treatment of AD. NFT consist of hyperphosphorylated tau protein and tau hyperphosphorylation reduces microtubule binding. Several protein kinases are discussed to be involved in tau hyperphosphorylation. We developed novel inhibitors of three protein kinases (gsk-3β, cdk5, and cdk1) and discussed their activity in relation to tau phosphorylation and on tau–tau interaction as a nucleation stage of a tau aggregation in cells. Strongest effects were observed for those inhibitors with effects on all the three kinases with emphasis on gsk-3β in nanomolar ranges.

scholarly journals Structure and Pathology of Tau Protein in Alzheimer Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Michala Kolarova ◽  
Francisco García-Sierra ◽  
Ales Bartos ◽  
Jan Ricny ◽  
Daniela Ripova
Keyword(s):  
Tau Protein ◽  
Posttranslational Modifications ◽  
Molecular Mechanisms ◽  
Human Life ◽  
Normal Structure ◽  
Proper Function ◽  
Global Trend ◽  
Clinicopathological Significance ◽  
And Function ◽  
Tau Aggregation

Alzheimer's disease (AD) is the most common type of dementia. In connection with the global trend of prolonging human life and the increasing number of elderly in the population, the AD becomes one of the most serious health and socioeconomic problems of the present. Tau protein promotes assembly and stabilizes microtubules, which contributes to the proper function of neuron. Alterations in the amount or the structure of tau protein can affect its role as a stabilizer of microtubules as well as some of the processes in which it is implicated. The molecular mechanisms governing tau aggregation are mainly represented by several posttranslational modifications that alter its structure and conformational state. Hence, abnormal phosphorylation and truncation of tau protein have gained attention as key mechanisms that become tau protein in a pathological entity. Evidences about the clinicopathological significance of phosphorylated and truncated tau have been documented during the progression of AD as well as their capacity to exert cytotoxicity when expressed in cell and animal models. This paper describes the normal structure and function of tau protein and its major alterations during its pathological aggregation in AD.

scholarly journals Doxycycline Interferes With Tau Aggregation and Reduces Its Neuronal Toxicity

2021 ◽  
Vol 13 ◽  
Author(s):  
Luciana Medina ◽  
Florencia González-Lizárraga ◽  
Antonio Dominguez-Meijide ◽  
Diego Ploper ◽  
Valeria Parrales ◽  
...  
Keyword(s):  
Tau Protein ◽  
Neurodegenerative Disorders ◽  
Dependent Manner ◽  
Free System ◽  
Neuronal Toxicity ◽  
A Cell ◽  
Disease Modifying ◽  
Time Required ◽  
Tau Aggregation ◽  
Dose Dependent

Tauopathies are neurodegenerative disorders with increasing incidence and still without cure. The extensive time required for development and approval of novel therapeutics highlights the need for testing and repurposing known safe molecules. Since doxycycline impacts α-synuclein aggregation and toxicity, herein we tested its effect on tau. We found that doxycycline reduces amyloid aggregation of the 2N4R and K18 isoforms of tau protein in a dose-dependent manner. Furthermore, in a cell free system doxycycline also prevents tau seeding and in cell culture reduces toxicity of tau aggregates. Overall, our results expand the spectrum of action of doxycycline against aggregation-prone proteins, opening novel perspectives for its repurposing as a disease-modifying drug for tauopathies.

Chaperonin as the normal controls and pathological anti-stress response in the human reproductive system

2016 ◽  
pp. 126-129
Author(s):  
M. Makarenko ◽  
◽  
D. Hovsyeyev ◽  
L. Sydoryk ◽  
◽  
...  
Keyword(s):  
Reproductive System ◽  
Stress Proteins ◽  
Physiological Stress ◽  
Protein Complexes ◽  
Reproductive Function ◽  
Intercellular Signaling ◽  
Toll Like Receptors ◽  
Wide Range ◽  
Protein Functions ◽  
And Function

Different kinds of physiological stress cause mass changes in the cells, including the changes in the structure and function of the protein complexes and in separate molecules. The protein functions is determined by its folding (the spatial conclusion), which depends on the functioning of proteins of thermal shock- molecular chaperons (HSPs) or depends on the stress proteins, that are high-conservative; specialized proteins that are responsible for the correct proteinaceous folding. The family of the molecular chaperones/ chaperonins/ Hsp60 has a special place due to the its unique properties of activating the signaling cascades through the system of Toll-like receptors; it also stimulates the cells to produce anti- inflammatory cytokines, defensins, molecules of cell adhesion and the molecules of MHC; it functions as the intercellular signaling molecule. The pathological role of Hsp60 is established in a wide range of illnesses, from diabetes to atherosclerosis, where Hsp60 takes part in the regulation of both apoptosis and the autoimmune processes. The presence of the HSPs was found in different tissues that are related to the reproductive system. Key words: molecular chaperons (HSPs), Toll-like receptors, reproductive function, natural auto antibody.

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