1,721,049 research outputs found
LRRK2 as a target for modulating immune system responses
Full text linkMutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene are associated with familial and sporadic cases of Parkinson's disease (PD) but are also found in patients with immune- related disorders, such as inflammatory bowel disease (IBD) and leprosy, linking LRRK2 to the immune system. Supporting this genetic evidence, in the last decade LRRK2 was robustly shown to modulate inflammatory responses at both systemic and central nervous system level. In this review, we recapitulate the role of LRRK2 in central and peripheral inflammation in PD and inflammatory disease models. Moreover, we discuss how LRRK2 inhibitors and anti- inflammatory drugs may be beneficial at reducing disease risk/progression in LRRK2-mutation carriers and manifesting PD patients, thus supporting LRRK2 as a promising disease-modifying PD strategy
Too much for your own good: Excessive dopamine damages neurons and contributes to Parkinson's disease: An Editorial Highlight for “Enhanced tyrosine hydroxylase activity induces oxidative stress, causes accumulation of autotoxic catecholamine metabolites, and augments amphetamine effects in vivo”
No full textDopamine dyshomeostasis is a driving factor of nigrostriatal degeneration in Parkinson's disease (PD). Accumulation of cytosolic dopamine at striatal projections results in the buildup of autoxidation products, which generates protein adducts and exacerbate oxidative stress. Moreover, an excessive rate of dopamine degradation results in accumulation of 3,4-dihydroxyphenylacetaldehyde (DOPAL), a toxic metabolite which rapidly reacts with other proteins. These events lead to protein misfolding and cross-linking as well as mitochondrial and lysosomal dysfunction, the main pathological mechanisms underscoring dopaminergic neuron loss in PD. In this issue of Journal of Neurochemistry, Vecchio et al. generated and characterized a new in vivo model of chronic dopamine accumulation through the overexpression of a hyperactive form of tyrosine hydroxylase (TH-HI), the rate-limiting step enzyme in dopamine biosynthesis. At 3–5 months of age, TH-HI mice displayed increased striatal dopamine content, exacerbated dopamine catabolism, and augmented responses to amphetamine. This correlated with enhanced oxidative stress and DOPAL buildup, highlighting a catechol-induced neurotoxic vicious cycle that may anticipate a parkinsonian-like phenotype in aged mice. This novel TH-HI animal model represents an exciting new tool to unravel the molecular mechanisms underlying dopamine disequilibrium, catecholamine autotoxicity, and neurodegeneration in PD. (Figure presented.)
Immunization therapies for Parkinson’s disease: state of the art and considerations for future clinical trials
No full textIntroduction: Advances in the understanding of the mechanisms that lead to Lewy body pathology in Parkinson's disease (PD) have yielded rationales for tackling neurodegeneration associated with α-Synuclein (α-Syn) misfolding, aggregation, and/or its related spreading. Immunization therapies targeting distinct α-Syn epitopes (conformational and linear) that aim to limit extracellular spread in the brain are now in development. Completed and ongoing studies have enrolled early PD patients without considering individual clinical differences and assume a common pathogenetic mechanism of the disease. Such approaches have led to disappointing results; this is most likely attributed to trial methodology and inadequate patient selection rather than underlying target biology. Areas covered: This review presents the status of immunotherapies that target α-Syn epitopes in PD. Mechanisms associated with neurodegeneration are examined along with the limitations of current antibody research strategies and ongoing clinical trials. Patient stratification based on disease progression is discussed and the article culminates with author suggestions on how to progress future clinical trials. Expert opinion: The efficacy of passive and active immunotherapies is inadequately evaluated in ongoing clinical trials where participating patients have various progression rates, genetic backgrounds, and clinical phenotypes. Future disease-modifying studies can overcome these limitations by enrolling patients based on progression pathways and genotypic contribution to disease manifestations
Mechanistic insight into the activity of tyrosinase from variable temperature studies in aqueous-organic solvent
No full textThe activity of mushroom tyrosinase on a representative series of phenolic and diphenolic substrates structurally related to tyrosine has been investigated in the mixed solvent of 34.4% methanol-glycerol (7/1 v/v) and 65.6% (v/v) aqueous 50 mM Hepes buffer pH 6.8 at various temperatures. The kinetic activation parameters ruling the enzymatic reactions and the thermodynamic parameters associated with the substrate binding process to the enzyme active species have been deduced from the temperature variation of the kcat and KM parameters. The activation free energy is dominated by the enthalpic term, which occurs in the relatively narrow range of 61 kJ mol-1 independent of substrate and reaction type (monophenolase or diphenolase). The activation entropies are small and generally negative and contribute no more than 10% to the activation free energy. The substrate binding parameters are characterized by large and negative enthalpy and entropy contributions, which are typically dictated by polar protein-substrate interactions. The substrate 4-hydroxyphenyl propionic acid exhibits a strikingly anomalous temperature dependence of the enzymatic oxidation rate, with deltaH 150 kJ mol-1 and deltaS 280 J K-1 mol-1, due to the fact that it can competitively bind to the enzyme through the phenol group, like the other substrates, or the carboxylate group, like carboxylic acid inhibitors. A kinetic model that includes the dual nature of substrate/inhibitor of this compound enables to account for the anomalous behavior
Metformin repurposing for parkinson disease therapy: Opportunities and challenges
Full text linkParkinson disease (PD) is a severe neurodegenerative disorder that affects around 2% of the population over 65 years old. It is characterized by the progressive loss of nigrostriatal dopaminergic neurons, resulting in motor disabilities of the patients. At present, only symptomatic cures are available, without suppressing disease progression. In this frame, the anti-diabetic drug metformin has been investigated as a potential disease modifier for PD, being a low-cost and generally welltolerated medication, which has been successfully used for decades in the treatment of type 2 diabetes mellitus. Despite the precise mechanisms of action of metformin being not fully elucidated, the drug has been known to influence many cellular pathways that are associated with PD pathology. In this review, we present the evidence in the literature supporting the neuroprotective role of metformin, i.e., autophagy upregulation, degradation of pathological α-synuclein species, and regulation of mitochondrial functions. The epidemiological studies conducted in diabetic patients under metformin therapy aimed at evaluating the correlation between long-term metformin consumption and the risk of developing PD are also discussed. Finally, we provide an interpretation for the controversial results obtained both in experimental models and in clinical studies, thus providing a possible rationale for future investigations for the repositioning of metformin for PD therapy
Impaired dopamine metabolism in Parkinson's disease pathogenesis
Full text linkA full understanding of Parkinson's Disease etiopathogenesis and of the causes of the preferential vulnerability of nigrostriatal dopaminergic neurons is still an unsolved puzzle. A multiple-hit hypothesis has been proposed, which may explain the convergence of familial, environmental and idiopathic forms of the disease. Among the various determinants of the degeneration of the neurons in Substantia Nigra pars compacta, in this review we will focus on the endotoxicity associated to dopamine dyshomeostasis. In particular, we will discuss the relevance of the reactive dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) in the catechol-induced neurotoxicity. Indeed, the synergy between the catechol and the aldehyde moieties of DOPAL exacerbates its reactivity, resulting in modification of functional protein residues, protein aggregation, oxidative stress and cell death. Interestingly, αSynuclein, whose altered proteostasis is a recurrent element in Parkinson's Disease pathology, is considered a preferential target of DOPAL modification. DOPAL triggers αSynuclein oligomerization leading to synapse physiology impairment. Several factors can be responsible for DOPAL accumulation at the pre-synaptic terminals, i.e. dopamine leakage from synaptic vesicles, increased rate of dopamine conversion to DOPAL by upregulated monoamine oxidase and decreased DOPAL degradation by aldehyde dehydrogenases. Various studies report the decreased expression and activity of aldehyde dehydrogenases in parkinsonian brains, as well as genetic variants associated to increased risk in developing the pathology. Thus, we discuss how the deregulation of these enzymes might be considered a contributing element in the pathogenesis of Parkinson's Disease or a down-stream effect. Finally, we propose that a better understanding of the impaired dopamine metabolism in Parkinson's Disease would allow a more refined patients stratification and the design of more targeted and successful therapeutic strategies
Jadavi S, Dante S, Civiero L, Sandre M, Bubacco L, Tosatto L, Bianchini P, Canale C, Diaspro A. Fluorescence labeling methods influence the aggregation process of α-syn in vitro differently. Nanoscale. 2023 May 11;15(18):8270-8277. doi: 10.1039/d2nr05487f. PMID: 37073868
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Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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