Neuroscience
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Review
Macromolecular Structures and Proteins Interacting with the Microtubule Associated Tau Protein.
It is well established that neurodegenerative diseases known as tauopathies are characterized by the presence of filamentous forms of phosphorylated tau protein inside neurons. However, the causal relationship between the initial symptoms of a particular disease and the molecular events affecting tau and leading to the appearance of tangles of filamentous forms of this protein remains unknown. Even the main function (or functions) of tau inside neurons is debatable and controversial. ⋯ I review here some of the most studied interactions of tau with different macromolecules and proteins, which can be classified according to the structural o functional unit within which the interaction works: Microtubule, Nuclear localization and DNA, Synaptic activity, RNA metabolism, Fats transport, Proteostasis, Amyloid Cascade Hypothesis, Mitochondria and Phosphorylation. Although this seems to be a broad spectrum of tau functions, interactome studies of tau reveal hundreds of plausible partners of tau, suggesting that it engages in an extensive network of interconnected regulatory interactions by means of its high capability to interact with all kinds of proteins and complex structures, combined with its vast number of post-translational modifications. I include also some thermodynamic data concerning the interaction of tau with some partners.
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Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expansion of CAG repeats in the Huntingtin (HTT) gene. Accumulating evidence suggests that the microtubule-associated tau protein participates in the pathogenesis of HD. Recently, we have identified changes in tau alternative splicing of exons 2, 3 and 10 in the putamen of HD patients (St-Amour et al, 2018). ⋯ On the other hand, higher 0N-tau (exclusion of exons 2 and 3) and lower 1N-tau (exclusion of exon 3) isoforms were seen exclusively in the putamen of HD individuals. Interestingly, investigated splicing factors were deregulated in both regions whereas exon 2 differences coincided with increased tau hyperphosphorylation, aggregation and markers of neurodegeneration. Overall, these results imply a differential regulation of tau exon 2 and exon 10 alternative splicing in HD putamen that could provide a useful biomarker or therapeutic target.
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In several forms of dementia, such as Alzheimer's disease, the cytoskeleton-associated protein tau undergoes proteolysis, giving rise to fragments that have a toxic impact on neuronal homeostasis. How these fragments interact with cellular structures, in particular with the cytoskeleton, is currently incompletely understood. Here, we developed a method, derived from a Tobacco Etch Virus (TEV) protease system, to induce controlled cleavage of tau at specific sites. ⋯ These distinct localizations were confirmed by expressing each separate fragment in cells. Some cleavages - in particular cleavages at amino-acid positions 124 or 256 - displayed a certain level of cellular toxicity, with an unusual relocalization of the N-terminal fragments to the nucleus. Based on the data presented here, inducible cleavage of tau by the TEV protease appears to be a valuable tool to reproduce tau fragmentation in cells and study the resulting consequences on cell physiology.
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Primary Tauopathies are a group of diseases defined by the accumulation of Tau, in which the alteration of this protein is the primary driver of the neurodegenerative process. In addition to the classical syndromes (Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and argyrophilic grain disease (AGD)), new entities, like primary age-related Tauopathy (PART), have been recently described. Except for the classical Richardson's syndrome phenotype in PSP, the correlation between the clinical picture of the primary Tauopathies and underlying pathology is poor. ⋯ These findings, pointing towards multifactorial causation, imply the participation of several pathways involving the myelin sheath integrity, the endoplasmic reticulum unfolded protein response, microglia, intracellular vesicle trafficking, or the ubiquitin-proteasome system. Additionally, GWAS show a high degree of genetic overlap across different Tauopathies. This is especially salient between PSP and CBD, but also GWAS studying the recently described PART phenotype shows genetic overlap with genes that promote Tau pathology and with others associated with Alzheimer's disease.