594 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
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
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
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
A cross-study transcriptional analysis of Parkinson's disease
No full textThe study of Parkinson's disease (PD), like other complex neurodegenerative disorders, is limited by access to brain tissue from patients with a confirmed diagnosis. Alternatively the study of peripheral tissues may offer some insight into the molecular basis of disease susceptibility and progression, but this approach still relies on brain tissue to benchmark relevant molecular changes against. Several studies have reported whole-genome expression profiling in post-mortem brain but reported concordance between these analyses is lacking. Here we apply a standardised pathway analysis to seven independent case-control studies, and demonstrate increased concordance between data sets. Moreover data convergence increased when the analysis was limited to the five substantia nigra (SN) data sets; this highlighted the down regulation of dopamine receptor signaling and insulin-like growth factor 1 (IGF1) signaling pathways. We also show that case-control comparisons of affected post mortem brain tissue are more likely to reflect terminal cytoarchitectural differences rather than primary pathogenic mechanisms. The implementation of a correction factor for dopaminergic neuronal loss predictably resulted in the loss of significance of the dopamine signaling pathway while axon guidance pathways increased in significance. Interestingly the IGF1 signaling pathway was also over-represented when data from non-SN areas, unaffected or only terminally affected in PD, were considered. Our findings suggest that there is greater concordance in PD whole-genome expression profiling when standardised pathway membership rather than ranked gene list is used for comparison
Messenger RNA oxidation occurs early in disease pathogenesis and promotes motor neuron degeneration in ALS.
No full textAccumulating evidence indicates that RNA oxidation is involved in a wide variety of neurological diseases and may be associated with neuronal deterioration during the process of neurodegeneration. However, previous studies were done in postmortem tissues or cultured neurons. Here, we used transgenic mice to demonstrate the role of RNA oxidation in the process of neurodegeneration.We demonstrated that messenger RNA (mRNA) oxidation is a common feature in amyotrophic lateral sclerosis (ALS) patients as well as in many different transgenic mice expressing familial ALS-linked mutant copper-zinc superoxide dismutase (SOD1). In mutant SOD1 mice, increased mRNA oxidation primarily occurs in the motor neurons and oligodendrocytes of the spinal cord at an early, pre-symptomatic stage. Identification of oxidized mRNA species revealed that some species are more vulnerable to oxidative damage, and importantly, many oxidized mRNA species have been implicated in the pathogenesis of ALS. Oxidative modification of mRNA causes reduced protein expression. Reduced mRNA oxidation by vitamin E restores protein expression and partially protects motor neurons.These findings suggest that mRNA oxidation is an early event associated with motor neuron deterioration in ALS, and may be also a common early event preceding neuron degeneration in other neurological diseases
Socio-economic inequality in small area use of elective total hip replacement in the English NHS in 1991 and 2001
No full textInternational evidence suggests that there are substantial socio-economic inequalities in the delivery of specialist health services, even in the UK and other high-income countries with publicly funded health systems (Goddard and Smith 2001, Dixon et al. 2003, Van Doorslaer, Koolman and Jones 2004, Van Doorslaer et al. 2000). Studies of total hip replacement in the English NHS have yielded particularly striking examples, given that hip replacement is such a common, effective and longestablished health technology. Administrative data show that people living in deprived areas are less likely to receive hip replacement (Chaturvedi and Ben-Shlomo 1995, Dixon et al. 2004) while survey data suggest they may be more likely to need it (Milner et al. 2004). However, previous studies have not examined change in inequality over time. This paper presents evidence on the change in socio-economic inequality in small area use of elective total hip replacement in the English NHS, comparing 1991 with 2001. This was a period of important large-scale health care reform in England, involving at least two significant reforms that might potentially have influenced socio-economic inequality in health care delivery: (1) the introduction and subsequent abolition of the Conservative “internal market” 1991-7, and (2) the introduction in 1995 of a revised NHS resource allocation formula designed to reduce geographical inequalities in health care delivery. Two datasets, for 1991 and 2001, were assembled from routine NHS data sources: Hospital Episode Statistics (HES) on hospital utilisation in England and the corresponding decennial National Censuses in 1991 and 2001. Both datasets contain information on over 8,000 electoral wards in England (over 95% of the total). To improve comparability, a common geography of frozen 1991 wards was adopted. The Townsend deprivation score was employed as an indicator of socio-economic status. Inequality was analysed in two ways. First, for comparability with previous small area studies of hip replacement, by using simple range measures based on indirectly age-sex standardised utilisation ratios (SURs) by deprivation quintile groups. Second, using concentration indices of deprivationrelated inequality in use based on indirectly age-sex standardised utilisation ratios for each individual small area. Each SUR is the observed use divided by the expected use, if each age and sex group in the study population had the same rates of use as the national population.
The group II p21-activated kinases as therapautic targets in LRRK2-related Parkinson’s disease
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