1,721,043 research outputs found
Leucine-rich repeat kinase 2 (LRRK2) and Parkinson’s disease: From genetics to pathobiology
No full textToo 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.)
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
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
Pathways to Parkinson's disease: a spotlight on 14-3-3 proteins
Full text link14-3-3s represent a family of highly conserved 30 kDa acidic proteins. 14-3-3s recognize and bind specific phospho-sequences on client partners and operate as molecular hubs to regulate their activity, localization, folding, degradation, and protein-protein interactions. 14-3-3s are also associated with the pathogenesis of several diseases, among which Parkinson's disease (PD). 14-3-3s are found within Lewy bodies (LBs) in PD patients, and their neuroprotective effects have been demonstrated in several animal models of PD. Notably, 14-3-3s interact with some of the major proteins known to be involved in the pathogenesis of PD. Here we first provide a detailed overview of the molecular composition and structural features of 14-3-3s, laying significant emphasis on their peculiar target-binding mechanisms. We then briefly describe the implication of 14-3-3s in the central nervous system and focus on their interaction with LRRK2, α-Synuclein, and Parkin, three of the major players in PD onset and progression. We finally discuss how different types of small molecules may interfere with 14-3-3s interactome, thus representing a valid strategy in the future of drug discovery
Presynaptic dysfunction in Parkinson's disease: a focus on LRRK2.
No full textPD (Parkinson's disease) is a common neurodegenerative disease clinically characterized by bradykinesia, rigidity and resting tremor. Recent studies have proposed that synaptic dysfunction, implicated in numerous studies of animal models of PD, might be a key factor in PD. The molecular defects that lead to PD progression might be hidden at the presynaptic neuron: in fact accumulating evidence has shown that the majority of the genes linked to PD play a critical role at the presynaptic site. In the present paper, we focus on the presynaptic function of LRRK2 (leucine-rich repeat kinase 2), a protein that mutated represents the main genetic cause of familial PD described to date. Neurotransmission relies on proper presynaptic vesicle trafficking; defects in this process, variation in dopamine flow and alteration of presynaptic plasticity have been reported in several animal models of LRRK2 mutations. Furthermore, impaired dopamine turnover has been described in presymptomatic LRRK2 PD patients. Thus, given the pathological events occurring at the synapses of PD patients, the presynaptic site may represent a promising target for early diagnostic therapeutic intervention
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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