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Untangling the Role of Tau in Physiology and Pathology

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Tau protein is a microtubule-associated protein (MAP) that under physiological conditions regulates MT dynamic behavior, spatial organization, and the axonal transport of organelles. Tau is primarily a neuronal protein encoded by a single gene that in the CNS can result in six major isoforms by alternative ...

Tau protein is a microtubule-associated protein (MAP) that under physiological conditions regulates MT dynamic behavior, spatial organization, and the axonal transport of organelles. Tau is primarily a neuronal protein encoded by a single gene that in the CNS can result in six major isoforms by alternative splicing. Tau binds to the carboxy-terminal region of tubulin through a MT-binding domain that contains four imperfect repeat domains. Alternative splicing of exon 10 leads to isoforms with three (3R) or four (4R) repeats. The 3R/4R ratio varies during development, with fetal brain expressing only 3R tau forms whereas equal amounts of 3R- and 4R-containing isoforms exist in the adult human brain, but also between different brain regions. 

More than three decades have passed since the seminal discovery that identified hyperphosphorylated tau protein as the main component of the paired helical filaments (PHF) present in the neurofibrillary tangles (NFT) isolated from the brain of Alzheimer’s disease (AD) patients. Since then, evidence has accumulated showing that post-translational modifications such as phosphorylation, glycosylation, acetylation, and truncation among others are pivotal in regulating tau function. Beyond its classical role as a MAP, recent advances in our understanding of tau cellular functions have revealed novel insights into its important role during pathogenesis and provided new potential therapeutic targets.

The occurrence of filamentous structures of aggregated, hyperphosphorylated tau is a constant finding in a group of neurodegenerative disorders collectively known as tauopathies, generally associated with synaptic loss and neuronal death. These are clinically, morphologically and biochemically heterogeneous disorders characterized by the deposition of abnormal tau protein in the brain. They are differentiated by distinct neuropathological phenotypes based on the involvement of different anatomical areas, cell types and presence of distinct isoforms of tau in the pathological deposits. Additional neurodegenerative conditions with diverse aetiologies may be associated with tau pathologies, including AD which is also characterized by amyloid-   position. Although individual non-AD primary tauopathies are rare disorders, collectively they have a significant impact. Development of rational tau-based drug therapies calls for a deeper understanding of the role of post-translational modifications in regulating tau pathways leading to dysfunction and neurodegeneration. Thus, the recognition of tau as a key player in the pathobiology of human neurodegenerative diseases has driven substantial efforts to understand its biological and pathological function.

This Research Topic aims to provide an overview of our current knowledge on the role of tau protein in the nervous system and during neurodegenerative tauopathies. Classical and atypical functions will be described and its involvement in the propagation of tau pathology in tauopathies. We welcome Original Research papers, Review articles and brief communications addressing the basic cellular and molecular mechanisms in which tau is involved as well as those underlying the neurodegenerative process and its therapeutic potential.


Keywords: dementia, alzheimer, tauopathies, tau, neurodegeneration


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