5,920 research outputs found
Glial phagocytic clearance in Parkinson’s disease
No full textAbstract An emerging picture suggests that glial cells’ loss of beneficial roles or gain of toxic functions can contribute to neurodegenerative conditions. Among glial cells, microglia and astrocytes have been shown to play phagocytic roles by engulfing synapses, apoptotic cells, cell debris, and released toxic proteins. As pathogenic protein accumulation is a key feature in Parkinson’s disease (PD), compromised phagocytic clearance might participate in PD pathogenesis. In contrast, enhanced, uncontrolled and potentially toxic glial clearance capacity could contribute to synaptic degeneration. Here, we summarize the current knowledge of the molecular mechanisms underlying microglial and astrocytic phagocytosis, focusing on the possible implication of phagocytic dysfunction in neuronal degeneration. Several endo-lysosomal proteins displaying genetic variants in PD are highly expressed by microglia and astrocytes. We also present the evidence that lysosomal defects can affect phagocytic clearance and discuss the therapeutic relevance of restoring or enhancing lysosomal function in PD
The sense of a beginning : Bakhtinian dialogic criticism on 'the gospel' in Mark.
No full textContemporary literary approaches have caused paradigm shifts in Biblical Studies in the last two decades as it appears in a great deal of Markan studies using narrative, reader-response, deconstructive, feminist, and new historicist approaches. However, literary studies on the Gospel of Mark have not taken into account theoretical questions underlying those approaches. As a result biblical critics are driven by new trends without ever having a chance to examine the critical baggage of the approaches. Consequently, there is a gap of communication between the old and the new one. Therefore this thesis is an attempt to meet the need of enhancing the quality of critical endeavour in biblical studies. In the light of most recent competing critical theories of literature, the first contribution of this thesis is the methodological finding that Bakhtinian dialogic criticism contains the most profound philosophical and practical foundations for solving some crucial theoretical problems in contemporary literary theories. It is a critique to a Saussurian linguistic system of language which becomes the very foundation of modern and postmodern literary criticism. Bakhtinian literary theory shifts the foundation of literary criticism on linguistic signs into the creative activity of the socio-cultural production of human communication. The shift into socio-cultural reality of language communication makes the notion of 'genre' very important to unlock the problem of text and context in literary studies. Since the Gospel of Mark has fascinated most literary critics in Biblical Studies, the problem of 'genre' of this gospel is chosen as the focus of this study. Secondly, as no agreement is reached as to what 'genre' the Gospel of Mark belongs, this thesis makes its contribution to the discussion by locating the problem of 'genre' of Mark in the context of genre theories and argues that the Bakhtinian suggestion to find genre in the socio-cultural sphere by analysing artistic intercourse between narrative agents in Mark has freed the competing analysis from the unresolved problem between the kerygmatic (content oriented) approach and the analogical (form oriented) approach. To achieve finding 'genre' in the socio-cultural sphere, this thesis focuses on Bakhtinian analysis of the process of artistic intercourse between narrative agents. The narrative communicative interrelationships between narrative agents is constructed in this thesis as a 'stereophonic' Bakhtinian model of dialogic communication. This model is an original contribution of this thesis for revising the traditional two dimensional model of narrative communication. Based on this dialogical model of communication, a special role is given to the Bakhtinian 'author-creator' in the realization process of genre through the interaction of polyphonic voices. Through the interaction of voices of the author-artist and the hero we are led to discover a relatively stable type of portraying and controlling reality in Mark, known as the genre of Roman 'satire'. The closest literary affinity is Satyrica by Petronius. This narrative strategy of 'satire' in Mark has its root in the prophetic discourse of the Old Testament which is saturating the speech of the narrator, John the Immerser, the centurion, the people, and even Jesus. Finally, the whole search for Markan 'genre' culminates in the analysis of the realization of genre through the analysis of Bakhtinian chronotope. The reality of the genre of Mark is its social reality that is in its role as dpxrj/ 'beginning'. As the Gospel of Mark proclaims itself as 'a beginning', it defines its claim of socio-cultural 'authority' in early Christianity. It is this 'sense of beginning' which enables the narrating and the narrated world of Mark to interact dialogically
Well-known trade mark protection: confusion in EU and Japan
No full textIn this thesis concerning the protection of well-known trade marks against confusion in the European Community Trade Mark (CTM) and Japanese trademark systems, the author critically considers the difficulties in comprehensively defining ‘well-known trade mark’ in the relevant international trade mark instruments. After critical analysis of various definitions of both ‘trade mark’ and ‘well-known trade mark’, she undertakes a comparison of the definitions of the parallel concepts of ‘trade mark of repute’ and ‘syuchi-syohyo’, and also undertakes an assessment as to the extent to which these trade marks are protected against confusion and kondo in the CTM and Japanese systems, respectively. It is concluded that the protection of well- known trade marks against confusion in the CTM and Japan cannot be said to be completely clear, and the author identifies some areas for legal refor
Leucine-rich repeat kinase-2 controls protein kinase A activation state through phosphodiesterase 4
No full textAbstract Background Evidence indicates a cross-regulation between two kinases, leucine-rich repeat kinase 2 (LRRK2) and protein kinase A (PKA). In neurons, LRRK2 negatively regulates PKA activity in spiny projecting neurons during synaptogenesis and in response to dopamine D1 receptor activation acting as an A-anchoring kinase protein (AKAP). In microglia cells, we showed that LRRK2 kinase activity negatively regulates PKA, impacting NF-κB p50 signaling and the inflammatory response. Here, we explore the molecular mechanism underlying the functional interaction between LRRK2 and PKA in microglia. Methods To understand which step of PKA signaling is modulated by LRRK2, we used a combination of in vitro and ex vivo systems with hyperactive or inactive LRRK2 as well as different readouts of PKA signaling. Results We confirmed that LRRK2 kinase activity acts as a negative regulator of PKA activation state in microglia. Specifically, we found that LRRK2 controls PKA by affecting phosphodiesterase 4 (PDE4) activity, modulating cAMP degradation, content, and its dependent signaling. Moreover, we showed that LRRK2 carrying the G2019S pathological mutation downregulates PKA activation causing a reduction of PKA-mediated NF-κB inhibitory signaling, which results, in turn, in increased inflammation in LRRK2 G2019S primary microglia upon α-synuclein pre-formed fibrils priming. Conclusions Overall, our findings indicate that LRRK2 kinase activity is a key regulator of PKA signaling and suggest PDE4 as a putative LRRK2 effector in microglia. In addition, our observations suggest that LRRK2 G2019S may favor the transition of microglia toward an overactive state, which could widely contribute to the progression of the pathology in LRRK2-related PD
Leucine-Rich Repeat Kinase 2 Mutations and Parkinson's Disease: Three Questions
No full textMutations in the gene encoding LRRK2 (leucine-rich repeat kinase 2) were first identified in 2004 and have since been shown to be the single most common cause of inherited Parkinson's disease. The protein is a large GTP-regulated serine/threonine kinase that additionally contains several protein–protein interaction domains. In the present review, we discuss three important, but unresolved, questions concerning LRRK2. We first ask: what is the normal function of LRRK2? Related to this, we discuss the evidence of LRRK2 activity as a GTPase and as a kinase and the available data on protein–protein interactions. Next we raise the question of how mutations affect LRRK2 function, focusing on some slightly controversial results related to the kinase activity of the protein in a variety of in vitro systems. Finally, we discuss what the possible mechanisms are for LRRK2-mediated neurotoxicity, in the context of known activities of the protein
The Gospel on the Margins: The Ideological Function of the Patristic Tradition on the Evangelist Mark
No full textIn spite of the virtually unanimous patristic opinion that the evangelist Mark was the interpreter of Peter, one of the most prestigious apostolic founding figures in Christian memory, the Gospel of Mark was mostly neglected in the patristic period. Not only is the text of Mark the least well represented of the canonical Gospels in terms of the number of patristic citations, commentaries and manuscripts, the explicit comments about the evangelist Mark reveal some ambivalence about its literary or theological value. In my survey of the reception of Mark from Papias of Hierapolis until Clement of Alexandria, I will argue that the reason why the patristic writers were hesitant to embrace the Gospel of Mark was that they perceived the text to be amenable to the Christological beliefs and social praxis of rival Christian factions. The patristic tradition about Mark may have little historical basis, but it had an important ideological function in appropriating the text in the name of an apostolic authority from the margins or periphery
Early presynaptic and late postsynaptic components contribute independently to Brain-Derived Neurotrophic Factor-induced synaptic plasticity
No full textTrophin-induced synaptic plasticity consists of both presynaptic and postsynaptic processes. The potential interdependence of these mechanisms and their temporal relationships are undefined. The synaptic vesicle protein Rab3A is required for the early, initial 10 min phase, but not for the later phase of BDNF-enhanced transmission. We now examine the temporal distinction and mechanistic relationships between these phases of BDNF action. Rab3A mutant cells did not exhibit increased mEPSC frequency in response to BDNF in cell culture, indicating absence of the presynaptic component. In contrast, BDNF enhanced post-synaptic glutamate-induced current in the mutant neurons as in the wildtype, indicating that the postsynaptic component of the response was intact. Finally, the postsynaptic NMDA receptor subunit NR2B was phosphorylated at Tyr1472 by BDNF in Rab3A knockouts, as previously shown in wildtype. Our results are the first to demonstrate that presynaptic and postsynaptic components of BDNF-enhanced synaptic activity are independent and temporally distinct.Peer reviewe
NRF2 activation restores disease related metabolic deficiencies in olfactory neurosphere-derived cells from patients with sporadic Parkinson's Disease
No full textExtent: 14p.Background: Without appropriate cellular models the etiology of idiopathic Parkinson’s disease remains unknown. We recently reported a novel patient-derived cellular model generated from biopsies of the olfactory mucosa (termed olfactory neurosphere-derived (hONS) cells) which express functional and genetic differences in a disease-specific manner. Transcriptomic analysis of Patient and Control hONS cells identified the NRF2 transcription factor signalling pathway as the most differentially expressed in Parkinson’s disease. Results: We tested the robustness of our initial findings by including additional cell lines and confirmed that hONS cells from Patients had 20% reductions in reduced glutathione levels and MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)- 2-(4-sulfophenyl)-2H-tetrazolium, inner salt] metabolism compared to cultures from healthy Control donors. We also confirmed that Patient hONS cells are in a state of oxidative stress due to higher production of H2O2 than Control cultures. siRNA-mediated ablation of NRF2 in Control donor cells decreased both total glutathione content and MTS metabolism to levels detected in cells from Parkinson’s Disease patients. Conversely, and more importantly, we showed that activation of the NRF2 pathway in Parkinson’s disease hONS cultures restored glutathione levels and MTS metabolism to Control levels. Paradoxically, transcriptomic analysis after NRF2 pathway activation revealed an increased number of differentially expressed mRNAs within the NRF2 pathway in L-SUL treated Patient-derived hONS cells compared to L-SUL treated Controls, even though their metabolism was restored to normal. We also identified differential expression of the PI3K/AKT signalling pathway, but only post-treatment. Conclusions: Our results confirmed NRF2 as a potential therapeutic target for Parkinson’s disease and provided the first demonstration that NRF2 function was inducible in Patient-derived cells from donors with uniquely varied genetic backgrounds. However, our results also demonstrated that the response of PD patient-derived cells was not co-ordinated in the same way as in Control cells. This may be an important factor when developing new therapeutics.Anthony L. Cook, Alejandra M. Vitale, Sugandha Ravishankar, Nicholas Matigian, Greg T. Sutherland, Jiangou Shan, Ratneswary Sutharsan, Chris Perry, Peter A. Silburn, George D. Mellick, Murray L. Whitelaw, Christine A. Wells, Alan Mackay-Sim and Stephen A. Woo
Should i publish in an open access journal?
No full textAn “author pays” publishing model is the only fair way to make biomedical research findings accessible to all, say Matthew Kurien and David S Sanders, but James J Ashton and R Mark Beattie worry that it can lead to bias in the evidence base towards commercially driven results
Hallmarks of neurodegenerative diseases
No full textDecades of research have identified genetic factors and biochemical pathways involved in neurodegenerative diseases (NDDs). We present evidence for the following eight hallmarks of NDD: pathological protein aggregation, synaptic and neuronal network dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, DNA and RNA defects, inflammation, and neuronal cell death. We describe the hallmarks, their biomarkers, and their interactions as a framework to study NDDs using a holistic approach. The framework can serve as a basis for defining pathogenic mechanisms, categorizing different NDDs based on their primary hallmarks, stratifying patients within a specific NDD, and designing multi-targeted, personalized therapies to effectively halt NDDs
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