1,720,990 research outputs found
Mitochondria Dysfunction and Neuroinflammation in Neurodegeneration: Who Comes First?
Full text link: Neurodegenerative diseases (NDs) encompass an assorted array of disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, each characterised by distinct clinical manifestations and underlying pathological mechanisms. While some cases have a genetic basis, many NDs occur sporadically. Despite their differences, these diseases commonly feature chronic neuroinflammation as a hallmark. Consensus has recently been reached on the possibility that mitochondria dysfunction and protein aggregation can mutually contribute to the activation of neuroinflammatory response and thus to the onset and progression of these disorders. In the present review, we discuss the contribution of mitochondria dysfunction and neuroinflammation to the aetiology and progression of NDs, highlighting the possibility that new potential therapeutic targets can be identified to tackle neurodegenerative processes and alleviate the progression of these pathologies
Is indeed the prion protein an Harlequin servant of "many" masters?
Full text linkTens of putative interacting partners of the cellular prion protein (PrP(C)) have been identified, yet the physiologic role of PrP(C) remains unclear. For the first time, however, a recent paper has demonstrated that the absence of PrP(C) produces a lethal phenotype. Starting from this evidence, here we discuss the validity of past and more recent literature supporting that, as part of protein platforms at the cell surface, PrP(C) may bridge extracellular matrix molecules and/or membrane proteins to intracellular signaling pathways
Almost a century of prion protein(s): From pathology to physiology, and back to pathology
No full textPrions are one of the few pathogens whose name is renowned at all population levels, after the dramatic
years pervaded by the fear of eating prion-infected food. If now this, somehow irrational, scare of bovine
meat inexorably transmitting devastating brain disorders is largely subdued, several prion-related issues
are still unsolved, precluding the design of therapeutic approaches that could slow, if not halt, prion
diseases.
One unsolved issue is, for example, the role of the prion protein (PrPC), whole conformational misfolding
originates the prion but whose physiologic reason d'etre in neurons, and in cells at large, remains
enigmatic. Preceded by a historical outline, the present review will discuss the functional pleiotropicity
ascribed to PrPC, and whether this aspect could fall, at least in part, into a more concise framework. It will
also be devoted to radically different perspectives for PrPC, which have been recently brought to the
attention of the scientific world with unexpected force. Finally, it will discuss the possible reasons
allowing an evolutionary conserved and benign protein, as PrPC is, to turn into a high affinity receptor for
pathologic misfolded oligomers, and to transmit their toxic message into neurons
Nucleolin: a cell portal for viruses, bacteria, and toxins
Full text linkThe main localization of nucleolin is the nucleolus, but this protein is present in multiple subcellular sites, and it is unconventionally secreted. On the cell surface, nucleolin acts as a receptor for various viruses, some bacteria, and some toxins. Aim of this review is to discuss the characteristics that make nucleolin able to act as receptor or co-receptor of so many and different pathogens. The important features that emerge are its multivalence, and its role as a bridge between the cell surface and the nucleus. Multiple domains, short linear motifs and post-translational modifications confer and modulate nucleolin ability to interact with nucleic acids, with proteins, but also with carbohydrates and lipids. This modular multivalence allows nucleolin to participate in different types of biomolecular condensates and to move to various subcellular locations, where it can act as a kind of molecular glue. It moves from the nucleus to the cell surface and can accompany particles in the reverse direction, from the cell surface into the nucleus, which is the destination of several pathogens to manipulate the cell in their favour
Prions and Prion-Like Pathogens in Neurodegenerative Disorders
Full text linkPrions are unique elements in biology, being able to transmit biological information from one organism to another in the absence of nucleic acids. They have been identified as self-replicating proteinaceous agents responsible for the onset of rare and fatal neurodegenerative disorders—known as transmissible spongiform encephalopathies, or prion diseases—which affect humans and other animal species. More recently, it has been proposed that other proteins associated with common neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease, can self-replicate like prions, thus sustaining the spread of neurotoxic entities throughout the nervous system. Here, we review findings that have contributed to expand the prion concept, and discuss if the involved toxic species can be considered bona fide prions, including the capacity to infect other organisms, or whether these pathogenic aggregates share with prions only the capability to self-replicate
Possible role for Ca2+ in the pathophysiology of the prion protein?
No full textTransmissible spongiform encephalopathies, or prion diseases, are lethal neurodegenerative disorders caused by the infectious agent named prion, whose main constituent is an aberrant conformational isoform of the cellular prion protein, PrP(C) . The mechanisms of prion-associated neurodegeneration and the physiologic function of PrP(C) are still unclear, although it is now increasingly acknowledged that PrP(C) plays a role in cell differentiation and survival. PrP(C) thus exhibits dichotomic attributes, as it can switch from a benign function under normal conditions to the triggering of neuronal death during disease. By reviewing data from models of prion infection and PrP-knockout paradigms, here we discuss the possibility that Ca(2+) is the hidden factor behind the multifaceted behavior of PrP(C) . By featuring in almost all processes of cell signaling, Ca(2+) might explain diverse aspects of PrP(C) pathophysiology, including the recently proposed one in which PrP(C) acts as a mediator of synaptic degeneration in Alzheimer's disease
A Twist in Yeast: New Perspectives for Studying TDP-43 Proteinopahies in S. cerevisiae
Full text linkTAR DNA-binding protein 43 kDa (TDP-43) proteinopathies are a group of neurodegenerative diseases (NDs) characterized by the abnormal accumulation of the TDP-43 protein in neurons and glial cells. These proteinopathies are associated with several NDs, including amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and some forms of Alzheimer’s disease. Yeast models have proven valuable in ND research due to their simplicity, genetic tractability, and the conservation of many cellular processes shared with higher eukaryotes. For several decades, Saccharomyces cerevisiae has been used as a model organism to study the behavior and toxicity of TDP-43, facilitating the identification of genes and pathways that either exacerbate or mitigate its toxic effects. This review will discuss evidence showing that yeast models of TDP-43 exhibit defects in proteostasis, mitochondrial function, autophagy, and RNA metabolism, which are key features of TDP-43-related NDs. Additionally, we will explore how modulating proteins involved in these processes reduce TDP-43 toxicity, aiding in restoring normal TDP-43 function or preventing its pathological aggregation. These findings highlight potential therapeutic targets for the treatment of TDP-43-related diseases
Ca2+ signalling: A common language for organelles crosstalk in Parkinson's disease
Full text linkParkinson's disease (PD) is a neurodegenerative disease caused by multifactorial pathogenic mechanisms. Familial PD is linked with genetic mutations in genes whose products are either associated with mitochondrial function or endo-lysosomal pathways. Of note, mitochondria are essential to sustain high energy demanding synaptic activity of neurons and alterations in mitochondrial Ca2+ signaling have been proposed as causal events for neurodegenerative process, although the mechanisms responsible for the selective loss of specific neuronal populations in the different neurodegenerative diseases is still not clear. Here, we specifically discuss the importance of a correct mitochondrial communication with the other organelles occurring at regions where their membranes become in close contact. We discuss the nature and the role of contact sites that mitochondria establish with ER, lysosomes, and peroxisomes, and how PD related proteins participate in the regulation/dysregulation of the tethering complexes. Unravelling molecular details of mitochondria tethering could contribute to identify specific therapeutic targets and develop new strategies to counteract the progression of the disease
Analisi funzionale di piD261/Bud32, una protein chinasi atipica di lievito conservata evolutivamente.
No full textAnalisi funzionale di piD261/Bud32, una protein chinasi atipica di lievito conservata evolutivamente
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