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Old and New Insights into the Role of Tau in...
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Old and New Insights into the Role of Tau in Neurodegeneration

A special issue of Brain Sciences (ISSN 2076-3425). This special issue belongs to the section "Molecular and Cellular Neuroscience".

Deadline for manuscript submissions: closed (5 April 2021) | Viewed by 24961

Special Issue Editors

Dr. Luisa Diomede

E-Mail Website
Guest Editor
Department of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy
Interests: molecular basis of human diseases; protein misfolding diseases; amyloid toxicity; C. elegans
Dr. Luca Colnaghi

E-Mail Website
Co-Guest Editor
Department of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156, Milan, Italy
Interests: neurodegeneration; genomic instability; tau

Special Issue Information

Dear Colleagues,

Tau is a natively unfolded microtubule-associated protein that is predominantly expressed in neurons. The cerebral accumulation of abnormal, aggregated filamentous assemblies of hyperphosphorylated tau represents a key feature in many neurodegenerative diseases which, for this reason, are grouped under the common name of tauopathies. Despite many decades of research, no effective therapy is currently available for these pathologies. In part, these challenges in treatment and diagnosis reflect our limited understanding—if any—of the specific processes driving neurodegeneration, including tau contribution.

A leading hypothesis suggests that the anatomical distribution of tau deposits, rather than the molecular identity of the protein, determines the nature of the tauopathy. However, biochemical studies indicate that both the degree of tau phosphorylation and the different protein isoforms can actively contribute to the clinical phenotype of the disease. Tau pathology has also been hypothesized to spread between synaptically connected neurons of the central nervous system through a prion-like mechanism by which pathological tau conformers seed misfolding of normal tau and/or other metastable proteins.

This Special Issue of Brain Sciences is dedicated to knowledge of the complex link between tau, tauopathies, aging, and neurodegeneration. We invite authors and research groups to submit review articles, research articles, or commentaries related to recent advances in these topics. Furthermore, we aim to investigate the prion-like properties of tau and its propagation, paying particular attention to the role of brain trauma in the onset and propagation of tau pathology. A new remarkable aspect of tau is its involvement in genetic instability, suggesting a relationship between cancer and neurodegenerative diseases. The activity of neuronal and non-neuronal tau in participating in the development of tumors and their sensitivity to chemotherapy will also be discussed.

Dr. Luisa Diomede
Dr. Luca Colnaghi
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Brain Sciences is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • tau
  • tauopathies
  • neurodegeneration
  • prion-like
  • traumatic brain injury
  • amyloid plaque
  • pharmacology
  • genomic instability

Published Papers (6 papers)

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Review

15 pages, 8046 KiB  
Review
Aging-Related Tau Astrogliopathy in Aging and Neurodegeneration
by Heather McCann, Briony Durand and Claire E. Shepherd
Brain Sci. 2021, 11(7), 927; https://doi.org/10.3390/brainsci11070927 - 13 Jul 2021
Cited by 6 | Viewed by 2877
Abstract
Astrocytes are of vital importance to neuronal function and the health of the central nervous system (CNS), and astrocytic dysfunction as a primary or secondary event may predispose to neurodegeneration. Until recently, the main astrocytic tauopathies were the frontotemporal lobar degeneration with tau [...] Read more.
Astrocytes are of vital importance to neuronal function and the health of the central nervous system (CNS), and astrocytic dysfunction as a primary or secondary event may predispose to neurodegeneration. Until recently, the main astrocytic tauopathies were the frontotemporal lobar degeneration with tau (FTLD-tau) group of disorders; however, aging-related tau astrogliopathy (ARTAG) has now been defined. This condition is a self-describing neuropathology mainly found in individuals over 60 years of age. Astrocytic tau accumulates with a thorny or granular/fuzzy morphology and is commonly found in normal aging as well as coexisting with diverse neurodegenerative disorders. However, there are still many unknown factors associated with ARTAG, including the cause/s, the progression, and the nature of any clinical associations. In addition to FTLD-tau, ARTAG has recently been associated with chronic traumatic encephalopathy (CTE), where it has been proposed as a potential precursor to these conditions, with the different ARTAG morphological subtypes perhaps having separate etiologies. This is an emerging area of exciting research that encompasses complex neurobiological and clinicopathological investigation. Full article
(This article belongs to the Special Issue Old and New Insights into the Role of Tau in Neurodegeneration)
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Figure 1

17 pages, 12483 KiB  
Review
The Significance of Tau Aggregates in the Human Brain
by Rudy J. Castellani
Brain Sci. 2020, 10(12), 972; https://doi.org/10.3390/brainsci10120972 - 11 Dec 2020
Cited by 14 | Viewed by 4470
Abstract
Neurofibrillary degeneration has attracted the attention of neuroscientists as both a hallmark of the disease and a subject for experimentation for more than a century. Recent studies implicate phosphorylated tau (p-tau) directly in neurodegenerative disease pathogenesis, although the human data continue to raise [...] Read more.
Neurofibrillary degeneration has attracted the attention of neuroscientists as both a hallmark of the disease and a subject for experimentation for more than a century. Recent studies implicate phosphorylated tau (p-tau) directly in neurodegenerative disease pathogenesis, although the human data continue to raise questions. P-tau accumulates with age in a roughly hierarchical manner, but avoids abundance in the neocortex unless co-occurring with amyloid-β. Neurodegenerative tauopathies tend to have p-tau morphologies that differ from aging and Alzheimer’s disease. Tau isoforms (3R vs. 4R) have a tendency to vary with tauopathy phenotype for unknown reasons. Selective vulnerability to p-tau and spatial-temporal disconnect from amyloid-β are evident in aging. P-tau assessment at autopsy involves tissue decomposition, which may skew microanatomical observations toward limited biological meaning. Two major consensus guidelines for interpreting p-tau at autopsy emphasize the challenges of clinicopathologic correlation, and reinforce the observation that regional neurodegeneration is a better correlate of clinical signs than is proteinopathy. Despite the proliferation of interesting and novel theories related to tau-mediated pathogenesis, the weight of the human observations suggests that neurofibrillary degeneration is an epiphenomenal hallmark of aging and disease rather than an epicenter of neurotoxicity. This is consistent with numerous tau-targeted therapeutic strategies that have been unsuccessful to date. Full article
(This article belongs to the Special Issue Old and New Insights into the Role of Tau in Neurodegeneration)
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Figure 1

15 pages, 4689 KiB  
Review
Tau and DNA Damage in Neurodegeneration
by Luca Colnaghi, Diego Rondelli, Marco Muzi-Falconi and Sarah Sertic
Brain Sci. 2020, 10(12), 946; https://doi.org/10.3390/brainsci10120946 - 7 Dec 2020
Cited by 20 | Viewed by 3685
Abstract
Neurodegenerative disorders are a family of incurable conditions. Among them, Alzheimer’s disease and tauopathies are the most common. Pathological features of these two disorders are synaptic loss, neuronal cell death and increased DNA damage. A key pathological protein for the onset and progression [...] Read more.
Neurodegenerative disorders are a family of incurable conditions. Among them, Alzheimer’s disease and tauopathies are the most common. Pathological features of these two disorders are synaptic loss, neuronal cell death and increased DNA damage. A key pathological protein for the onset and progression of the conditions is the protein tau, a microtubule-binding protein highly expressed in neurons and encoded by the MAPT (microtubule-associated protein tau) gene. Tau is predominantly a cytosolic protein that interacts with numerous other proteins and molecules. Recent findings, however, have highlighted new and unexpected roles for tau in the nucleus of neuronal cells. This review summarizes the functions of tau in the metabolism of DNA, describing them in the context of the disorders. Full article
(This article belongs to the Special Issue Old and New Insights into the Role of Tau in Neurodegeneration)
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Figure 1

24 pages, 1412 KiB  
Review
Emerging Evidences for an Implication of the Neurodegeneration-Associated Protein TAU in Cancer
by Stéphanie Papin and Paolo Paganetti
Brain Sci. 2020, 10(11), 862; https://doi.org/10.3390/brainsci10110862 - 16 Nov 2020
Cited by 26 | Viewed by 3124
Abstract
Neurodegenerative disorders and cancer may appear unrelated illnesses. Yet, epidemiologic studies indicate an inverse correlation between their respective incidences for specific cancers. Possibly explaining these findings, increasing evidence indicates that common molecular pathways are involved, often in opposite manner, in the pathogenesis of [...] Read more.
Neurodegenerative disorders and cancer may appear unrelated illnesses. Yet, epidemiologic studies indicate an inverse correlation between their respective incidences for specific cancers. Possibly explaining these findings, increasing evidence indicates that common molecular pathways are involved, often in opposite manner, in the pathogenesis of both disease families. Genetic mutations in the MAPT gene encoding for TAU protein cause an inherited form of frontotemporal dementia, a neurodegenerative disorder, but also increase the risk of developing cancer. Assigning TAU at the interface between cancer and neurodegenerative disorders, two major aging-linked disease families, offers a possible clue for the epidemiological observation inversely correlating these human illnesses. In addition, the expression level of TAU is recognized as a prognostic marker for cancer, as well as a modifier of cancer resistance to chemotherapy. Because of its microtubule-binding properties, TAU may interfere with the mechanism of action of taxanes, a class of chemotherapeutic drugs designed to stabilize the microtubule network and impair cell division. Indeed, a low TAU expression is associated to a better response to taxanes. Although TAU main binding partners are microtubules, TAU is able to relocate to subcellular sites devoid of microtubules and is also able to bind to cancer-linked proteins, suggesting a role of TAU in modulating microtubule-independent cellular pathways associated to oncogenesis. This concept is strengthened by experimental evidence linking TAU to P53 signaling, DNA stability and protection, processes that protect against cancer. This review aims at collecting literature data supporting the association between TAU and cancer. We will first summarize the evidence linking neurodegenerative disorders and cancer, then published data supporting a role of TAU as a modifier of the efficacy of chemotherapies and of the oncogenic process. We will finish by addressing from a mechanistic point of view the role of TAU in de-regulating critical cancer pathways, including the interaction of TAU with cancer-associated proteins. Full article
(This article belongs to the Special Issue Old and New Insights into the Role of Tau in Neurodegeneration)
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Graphical abstract

29 pages, 1814 KiB  
Review
Pharmacological Modulators of Tau Aggregation and Spreading
by Antonio Dominguez-Meijide, Eftychia Vasili and Tiago Fleming Outeiro
Brain Sci. 2020, 10(11), 858; https://doi.org/10.3390/brainsci10110858 - 13 Nov 2020
Cited by 19 | Viewed by 6955
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Old and New Insights into the Role of Tau in Neurodegeneration)
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Figure 1

17 pages, 1141 KiB  
Review
Caenorhabditis elegans Models to Investigate the Mechanisms Underlying Tau Toxicity in Tauopathies
by Carmina Natale, Maria Monica Barzago and Luisa Diomede
Brain Sci. 2020, 10(11), 838; https://doi.org/10.3390/brainsci10110838 - 11 Nov 2020
Cited by 10 | Viewed by 3110
Abstract
The understanding of the genetic, biochemical, and structural determinants underlying tau aggregation is pivotal in the elucidation of the pathogenic process driving tauopathies and the design of effective therapies. Relevant information on the molecular basis of human neurodegeneration in vivo can be obtained [...] Read more.
The understanding of the genetic, biochemical, and structural determinants underlying tau aggregation is pivotal in the elucidation of the pathogenic process driving tauopathies and the design of effective therapies. Relevant information on the molecular basis of human neurodegeneration in vivo can be obtained using the nematode Caenorhabditis elegans (C. elegans). To this end, two main approaches can be applied: the overexpression of genes/proteins leading to neuronal dysfunction and death, and studies in which proteins prone to misfolding are exogenously administered to induce a neurotoxic phenotype. Thanks to the easy generation of transgenic strains expressing human disease genes, C. elegans allows the identification of genes and/or proteins specifically associated with pathology and the specific disruptions of cellular processes involved in disease. Several transgenic strains expressing human wild-type or mutated tau have been developed and offer significant information concerning whether transgene expression regulates protein production and aggregation in soluble or insoluble form, onset of the disease, and the degenerative process. C. elegans is able to specifically react to the toxic assemblies of tau, thus developing a neurodegenerative phenotype that, even when exogenously administered, opens up the use of this assay to investigate in vivo the relationship between the tau sequence, its folding, and its proteotoxicity. These approaches can be employed to screen drugs and small molecules that can interact with the biogenesis and dynamics of formation of tau aggregates and to analyze their interactions with other cellular proteins. Full article
(This article belongs to the Special Issue Old and New Insights into the Role of Tau in Neurodegeneration)
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