Neuroscience
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Reconsolidation results in the restabilisation, and thus persistence, of a memory made labile by retrieval, and interfering with this process is thought to enable modification or weakening of the original trace. As such, reconsolidation-blockade has been a focus of research aiming to target the maladaptive memories underlying mental health disorders, including post-traumatic stress disorder and drug addiction. Current first-line therapies are not effective for all patients, and a substantial proportion of those for whom therapies are effective later relapse. ⋯ These include factors such as the age and strength of memory, and can broadly be divided into two categories: intrinsic features of the targeted memory itself, and parameters of the reactivation procedure used. With maladaptive memory characteristics inevitably varying amongst individuals, manipulation of the other limitations imposed by procedural variables have been explored to circumvent the boundary conditions on reconsolidation. Although several apparently discrepant results remain to be reconciled and these limitations yet to be truly defined, many studies have produced successful results which encouragingly demonstrate that boundary conditions may be overcome using various proposed strategies to enable translation of a reconsolidation-based intervention to clinical use.
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Tauopathies are a group of heterogeneous neurodegenerative conditions characterized by the deposition of abnormal tau protein in the brain. The underlying mechanisms that contribute to the accumulation of tau in these neurodegenerative diseases are multifactorial; nonetheless, there is a growing awareness that dysfunction of endosome-lysosome pathways is a pivotal factor. BCL2 associated athanogene 3 (BAG3) is a multidomain protein that plays a key role in maintaining neuronal proteostasis. ⋯ High throughput screens of BAG3 interactors have identified key players in the vacuolar system; these include clathrin and regulators of small GTPases. These findings suggest that BAG3 is an important regulator of endocytic pathways. In this commentary, we discuss the potential mechanisms by which BAG3 regulates the vacuolar system and tau proteostasis.
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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.
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Tau is a well-known microtubule-associated protein related to its cytoplasmic localization in a neuronal cell. However, tau has been located at the cell nucleus where it could be a nucleic acid-associated protein by its preferential binding to DNA sequences present in the nucleolus and pericentromeric heterochromatin. This less well-known localization of tau could not be trivial, since during aging, an increase in the amount of nuclear tau takes place and it may be related to the described role of tau in the activation of transposons and further aging acceleration.
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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.