Abstract
Tau is a brain microtubule-associated protein that directly binds to a microtubule and dynamically regulates its structure and function. Under pathological conditions, tau self-assembles into filamentous structures that end up forming neurofibrillary tangles. Prominent tau neurofibrillary pathology is a common feature in a number of neurodegenerative disorders, collectively referred to as tauopathies, the most common of which is Alzheimer’s disease (AD). Beyond its classical role as a microtubule-associated protein, recent advances in our understanding of tau cellular functions have revealed novel insights into their important role during pathogenesis and provided potential novel therapeutic targets. Regulation of tau behavior and function under physiological and pathological conditions is mainly achieved through post-translational modifications, including phosphorylation, glycosylation, acetylation, and truncation, among others, indicating the complexity and variability of factors influencing regulation of tau toxicity, all of which have significant implications for the development of novel therapeutic approaches in various neurodegenerative disorders. A more comprehensive understanding of the molecular mechanisms regulating tau function and dysfunction will provide us with a better outline of tau cellular networking and, hopefully, offer new clues for designing more efficient approaches to tackle tauopathies in the near future.
Highlights
From an analytical point of view, the three main cell compartments—nucleus, cytoplasm, and membrane—have been mostly studied in the past century by three different scientific disciplines: molecular biology, cell biology, and cell signaling
We have reviewed recent developments in tau biology relevant to Alzheimer’s disease (AD) and tauopathies
It has become increasingly clear that, apart from the well-established intracellular functions of tau in microtubule stabilization and axonal transport, intracellular and extracellular tau have important signaling roles that could contribute to the neurodegenerative process in AD and related tauopathies
Summary
From an analytical point of view, the three main cell compartments—nucleus, cytoplasm, and membrane—have been mostly studied in the past century by three different scientific disciplines: molecular biology (nucleus), cell biology (cytoplasm), and cell signaling (membrane). During the 1970s and 1980s, in an effort to introduce the molecular biology to the study of the cell cytoplasm, proteins located at the cytoplasm were analyzed. These were mainly those involved in the components of the cytoskeleton: microtubules, microfilaments, and intermediate filaments. Brain microtubules can be isolated in vitro and they are composed mostly (about 90%) of tubulin subunits, with the remaining 10% consisting of the microtubule-associated proteins (MAPs) that, according to the order of its electrophoretic mobility, were classified as MAP1, MAP2, and tau [2]. We review and discuss recent findings about the role of both function and dysfunction of tau protein
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