Neuroscience
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Review
The Plasma Membrane Ca2+-ATPase, a Molecular Target for Tau-induced Cytosolic Calcium Dysregulation.
Disruption of calcium (Ca2+) homeostasis is emerging as a prevalent feature of aging and aging-associated neurodegenerative diseases, including Alzheimer's disease (AD), the most common type of tauopathy. This disease is characterized by the combined presence of extracellular neuritic plaques composed by amyloid β-peptides (Aβ) and neurofibrillary tangles of tau. The association of calcium dyshomeostasis with Aβ has been extensively studied, however its link with tau has been less investigated. Thus, this review will concentrate on the functional link between tau and the plasma membrane Ca2+ pump (PMCA) and other membrane proteins involved in the regulation of intracellular calcium and/or its association with neurodegeneration.
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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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Tauopathies are a group of neurodegenerative diseases among which are many of the most prevalent and with higher incidence worldwide, such as Alzheimer's disease (AD). According to the World Health Organization, this set of diseases will continue to increase their incidence, affecting millions of people by 2050. All of them are characterized by aberrant aggregation of tau protein in neurons and glia that are distributed in different brain regions according to their susceptibility. ⋯ Despite this, it has not been emphasized how the glial inclusions of tau in this cell type directly affect this and many other essential functions, whose alterations have been related to the development of tauopathies. In this way, this review shows how tau inclusions in glia influence the synaptic dysfunctions that result in the cognitive symptoms characteristic of tauopathies. Thus, the mechanisms affected by inclusions in neurons, astrocytes, and oligodendrocytes are unraveled.
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Gut microbiota represents a diverse and dynamic population of microorganisms harbouring the gastrointestinal tract, which influences host health and disease. Bacterial colonization of the gastrointestinal tract begins at birth and changes throughout life, with age being one of the conditioning factors for its vitality. Aging is also a primary risk factor for most neurodegenerative diseases. ⋯ Data from clinical studies as well as the link between microbiome and clinical determinants of AD are particularly emphasized. Further, relationships between gut microbiota and age-dependent epigenetic changes and other neurological disorders are also described. Together, all this evidence suggests that, in some sense, gut microbiota can be seen as an additional hallmark of human aging and neurodegeneration.