250 research outputs found
The multiple affinities of alpha-dystroglycan
No full textThe dystroglycan (DG) adhesion complex is formed by the peripheral a-DG and the transmembrane a-DG,
both originating from the same precursor. a-DG plays a crucial role for tissue stability since it binds with high affinity a
variety of proteins and proteoglycans in many different cell types. One common molecular feature of most of the a-DG
ligands is the presence of LG domains that are likely to interact with some of the carbohydrates protruding from the
mucin-like region of a-DG. Every tissue is supposed to produce a specific a-DG harboring a particular sugar moiety that
will enable it to bind a specific ligand, but often several a-DG ligands are co-expressed within the same tissue. It is therefore very important to assess all these different interactions, ultimately measuring the affinity constants (KDs) underlying
them. Herein, we present an updated list of a-DG interactors, including non LG domains containing ligands, offering both
a historic perspective on the original contributions offered by several laboratories and an update on the different techniques used and the KD values obtained so far. For the cure of some muscular dystrophies, the reinstatement of a prominent affinity between a-DG and one of its vicarious ligands is becoming an increasingly popular choice for strengthening
the basement membrane-tissue connection. An update on the current available information about a-DG’s multiple, and often “concomitant” affinities, may be of interest for those wishing to better direct their molecular therapy approaches. A final paragraph is dedicated to comment on the evidence that an increase in affinity is not always advantageous
Role of gelatinases in pathological and physiological processes involving the dystrophin-glycoprotein complex
No full textDystrophin is a cytosolic protein belonging to a membrane-spanning glycoprotein complex, called dystrophin-glycoprotein complex (DGC) that is expressed in many tissues, especially in skeletal muscle and in the nervous system. The DGC connects the cytoskeleton to the extracellular matrix and, although none of the proteins of the DGC displays kinase or phosphatase activity, it is involved in many signal transduction pathways. Mutations in some components of the DGC are linked to many forms of inherited muscular dystrophies. In particular, a mutation in the dystrophin gene, leading to a complete loss of the protein, provokes one of the most prominent muscular dystrophies, the Duchenne muscular dystrophy, which affects 1 out of 3500 newborn males. What is observed in these circumstances, is a dramatic alteration of the expression levels of a multitude of metalloproteinases (MMPs), a family of extracellular Zn(2+)-dependent endopeptidases, in particular of MMP-2 and MMP-9, also called gelatinases. Indeed, the enzymatic activity of MMP-2 and MMP-9 on dystroglycan, an important member of the DGC, plays a significant role also in physiological processes taking place in the central and peripheral nervous system. This mini-review discusses the role of MMP-2 and MMP-9, in physiological as well as pathological processes involving members of the DGC.</p
Molecular mechanisms underlying muscle wasting in huntington’s disease
No full textHuntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by pathogenic expansions of the triplet cytosine-adenosine-guanosine (CAG) within the Huntingtin gene. These expansions lead to a prolongation of the poly-glutamine stretch at the N-terminus of Huntingtin causing protein misfolding and aggregation. Huntingtin and its pathological variants are widely expressed, but the central nervous system is mainly affected, as proved by the wide spectrum of neurological symptoms, including behavioral anomalies, cognitive decline and motor disorders. Other hallmarks of HD are loss of body weight and muscle atrophy. This review highlights some key elements that likely provide a major contribution to muscle atrophy, namely, alteration of the transcriptional processes, mitochondrial dysfunction, which is strictly correlated to loss of energy homeostasis, inflammation, apoptosis and defects in the processes responsible for the protein quality control. The improvement of muscular symptoms has proven to slow the disease progression and extend the life span of animal models of HD, underlining the importance of a deep comprehension of the molecular mechanisms driving deterioration of muscular tissue
From adhesion complex to signaling hub: the dual role of dystroglycan
No full textDystroglycan (DG) is a transmembrane protein widely expressed in multiple cells and tissues. It is formed by two subunits, alpha- and beta-DG, and represents a molecular bridge between the outside and the inside of the cell, which is essential for the mechanical and structural stability of the plasma membrane. The alpha-subunit is a cell-surface protein that binds to the extracellular matrix (ECM) and is tightly associated with the plasma membrane via a non-covalent interaction with the beta-subunit, which, in turn, is a transmembrane protein that binds to the cytoskeletal actin. DG is a versatile molecule acting not only as a mechanical building block but also as a modulator of outside-inside signaling events. The cytoplasmic domain of beta-DG interacts with different adaptor and cytoskeletal proteins that function as molecular switches for the transmission of ECM signals inside the cells. These interactions can modulate the involvement of DG in different biological processes, ranging from cell growth and survival to differentiation and proliferation/regeneration. Although the molecular events that characterize signaling through the ECM-DG-cytoskeleton axis are still largely unknown, in recent years, a growing list of evidence has started to fill the gaps in our understanding of the role of DG in signal transduction. This mini-review represents an update of recent developments, uncovering the dual role of DG as an adhesion and signaling molecule that might inspire new ideas for the design of novel therapeutic strategies for pathologies such as muscular dystrophy, cardiomyopathy, and cancer, where the DG signaling hub plays important roles
The missense mutation C667F in murine β-dystroglycan causes embryonic lethality, myopathy and blood-brain barrier destabilization
No full textDystroglycan (DG) is an extracellular matrix receptor consisting of an α- and a β-DG subunit encoded by the DAG1 gene. The homozygous mutation (c.2006G>T, p.Cys669Phe) in β-DG causes Muscle-Eye-Brain disease with multicystic leukodystrophy in humans. In a mouse model of this primary dystroglycanopathy, approximately two-thirds of homozygous embryos fail to develop to term. Mutant mice that are born undergo a normal postnatal development but show a late-onset myopathy with partially penetrant histopathological changes and an impaired performance on an activity wheel. Their brains and eyes are structurally normal, but the localization of mutant β-DG is altered in the glial perivascular endfeet resulting in a perturbed protein composition of the blood-brain and blood-retina barrier. In addition, α- and β-DG protein levels are significantly reduced in muscle and brain of mutant mice. Due to the partially penetrant developmental phenotype of the C669F-β-DG mice, they represent a novel and highly valuable mouse model to study the molecular effects of β-DG functional alterations both during embryogenesis and in mature muscle, brain and eye, and to gain insight into the pathogenesis of primary dystroglycanopathies
Osservazioni sull’indipendenza dell’esperienza immediata: da Frege alla «fenomenologia sperimentale» di Paolo Bozzi
No full textPaolo Bozzi developed his «experimental phenomenology» from the Gestalt psychology tradition, particularly from Gaetano Kanizsa’s method. The distinction between «phenomenal description» and «causal explanation» of the «perception» springs up from the analysis of Bozzi’s «S-D psychophysical scheme». What Frege, who was well-known by Bozzi, deals with in paragraph 71 of The Thought theoretically mirrors what is outlined in the Scheme and could also be intended as its source. The juxtaposition between a «science of observable things» or «experimental phenomenology» – conceived as a science which is autonomous from what happens in the brain – and logics, which is set up autonomously from the thinking processes, is a programmatic element that is openly indicated by the author. Frege’s anti-psychologism and realism are both widely shared by Bozzi. The realism and the «naïve physics» Bozzi was a pioneer of lie at the basis of the so-called «New Realism». The following essay aims to localize and highlight some theoretical implications – up to their phenomenological origins – which can be detected particularly in paragraph 71 of The Thought. The present work tries to sketch out the boundaries and the autonomy of the «first person» perceptive experience and to define the scientific explanation that we can give of it. The distinction between science and experience, and the autonomy of experience from science and of the immediate experience of the content of consciousness from neuroscience, entail the impossibility of a naturalization of the phenomenological experience. In the examples taken from Frege can be found a theoretical bridge which connects the Gestalt perceptological tradition, Wittgenstein’s investigations of the philosophy of psychology, and the so called «New Realism».</p
The pressure of experience pushes language into poetry. Fact, fistion, autofiction, and surfiction in Herta Müller's work
No full textOver the last fifteen years, the emergence of groundbreaking work on trauma in literature and critical theory has made a profound impact both within and beyond the field of literature. Müller surely represents and reflects upon the traumatic events of twentieth-century Europe, as well as the cultural diversity of East Central Europe; she feels compelled to write about them and to show her aversion to all forms of authoritarian rule. There is no doubt that Müller’s all-pervading concern with totalitarianism; her commitment to uncover political and cultural “truths” distinguishes her as an author for whom personal integrity is everything. In fact, Müller’s work is not only structured by a narrative of trauma, articulated with increasing directness, but also by a remarkable lyrical intensity, that manages to preserve a substantial, enriching imaginative space for the reader within such unremitting anger. Thus the reader is not only confronted with “autofiction,” as Müller herself suggests, but also with something akin to “surfiction,” a term coined by American author and critic Raymond Federman. I argue that this characteristic feature is not only a mark of her aesthetic achievement or her consummate artistry, but also the key to her convincing critical voice
Osservazioni sull’indipendenza dell’esperienza immediata: da Frege alla «fenomenologia sperimentale» di Paolo Bozzi
No full textPaolo Bozzi developed his «experimental phenomenology» from the Gestalt psychology tradition, particularly from Gaetano Kanizsa’s method. The distinction between «phenomenal description» and «causal explanation» of the «perception» springs up from the analysis of Bozzi’s «S-D psychophysical scheme». What Frege, who was well-known by Bozzi, deals with in paragraph 71 of The Thought theoretically mirrors what is outlined in the Scheme and could also be intended as its source. The juxtaposition between a «science of observable things» or «experimental phenomenology» – conceived as a science which is autonomous from what happens in the brain – and logics, which is set up autonomously from the thinking processes, is a programmatic element that is openly indicated by the author. Frege’s anti-psychologism and realism are both widely shared by Bozzi. The realism and the «naïve physics» Bozzi was a pioneer of lie at the basis of the so-called «New Realism». The following essay aims to localize and highlight some theoretical implications – up to their phenomenological origins – which can be detected particularly in paragraph 71 of The Thought. The present work tries to sketch out the boundaries and the autonomy of the «first person» perceptive experience and to define the scientific explanation that we can give of it. The distinction between science and experience, and the autonomy of experience from science and of the immediate experience of the content of consciousness from neuroscience, entail the impossibility of a naturalization of the phenomenological experience. In the examples taken from Frege can be found a theoretical bridge which connects the Gestalt perceptological tradition, Wittgenstein’s investigations of the philosophy of psychology, and the so called «New Realism»
A second Ig-like domain identified in dystroglycan by molecular modelling and dynamics
No full textDystroglycan (DG) is a cell surface receptor which is composed of two subunits that interact noncovalently, namely alpha- and beta-DG. In skeletal muscle, DG is the central component of the dystrophin-glycoprotein complex (DGC) that anchors the actin cytoskeleton to the extracellular matrix. To date only the three-dimensional structure of the N-terminal region of alpha-DG has been solved by X-ray crystallography. To expand such a structural analysis, a theoretical molecular model of the murine alpha-DG C-terminal region was built based on folding recognition/threading techniques. Although there is no a significant (<30\%) sequence homology with the N-terminal region of alpha-DG, protein fold recognition methods found a significant resemblance to the alpha-DG N-terminal crystallographic structure. Our in silico structural prediction identified two subdomains in this region. Amino acid residues similar to 500-600 of alpha-DG were predicted to adopt an immunoglobulin-like (Ig-like) beta-sandwich fold. Such modeled domain includes the beta-DG binding epitope of alpha-DG and, confirming our previous experimental results, suggests that the linear epitope (residues 550-565) assumes a beta-strand conformation. The remaining segment of the alpha-DG C-terminal region (residues 601-653) is organized in a coil-helix-coil motif. A 20-ns molecular dynamics simulation in explicit water solvent provided support to the predicted Ig-like model structure. The identification of a second Ig-like domain in DG represents another important step towards a full structural and functional description of the alpha/beta DG interface. Preliminary characterization of a novel recombinant peptide (505-600) encompassing this second lg-like domain demonstrates that it is soluble and stable, further corroborating our in silico analysi
Einstein's rocky picture show. Einstein überquert die Elbe bei Hamburg di Siegfried Lenz
No full textIn his short story, Siegfried Lenz explores the possibilities of language, time, and the different art forms through a photograph of a ferry crossing the Elbe near Hamburg. The «snapshot to be read», as the author calls it, relates the «unexpected suspension» of time and space caused by the appearance on it of an old man with a slouch-hat, long grey hair, and a pipe, who seems to control flow and movement and who turns out to be Albert Einstein. Instantly recognizable, like Charlie Chaplin’s Little Tramp, the embodiment of pure intellect, the genius among geniuses is here, ironically, a magician. His thaumaturgic presence reminds us of the existence of «certain uncertainties in what we perceive and say». Playing with the theory of relativity, Lenz experiments with writing and transfers Einstein’s space-time continuum into a language-time continuum. Thus, the reader is invited to enter into the photograph and become aware of its limits
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