Mitochondrial Fusion/Fission, Transport and Autophagy in Parkinson's Disease: When Mitochondria Get Nasty

Understanding the molecular basis of Parkinson's disease (PD) has proven to be a major challenge in the field of neurodegenerative diseases. Although several hypotheses have been proposed to explain the molecular mechanisms underlying the pathogenesis of PD, a growing body of evidence has highlighted the role of mitochondrial dysfunction and the disruption of the mechanisms of mitochondrial dynamics in PD and other parkinsonian disorders. In this paper, we comment on the recent advances in how changes in the mitochondrial function and mitochondrial dynamics (fusion/fission, transport, and clearance) contribute to neurodegeneration, specifically focusing on PD. We also evaluate the current controversies in those issues and discuss the role of fusion/fission dynamics in the mitochondrial lifecycle and maintenance. We propose that cellular demise and neurodegeneration in PD are due to the interplay between mitochondrial dysfunction, mitochondrial trafficking disruption, and impaired autophagic clearance

Microtubule Depolymerization Potentiates Alpha-Synuclein Oligomerization

Parkinson's disease (PD) is associated with perturbed mitochondria function and alpha-synuclein fibrillization. We evaluated potential mechanistic links between mitochondrial dysfunction and alpha-synuclein aggregation. We studied a PD cytoplasmic hybrid (cybrid) cell line in which platelet mitochondria from a PD subject were transferred to NT2 neuronal cells previously depleted of endogenous mitochondrial DNA. Compared to a control cybrid cell line, the PD line showed reduced ATP levels, an increased free/polymerized tubulin ratio, and alpha-synuclein oligomer accumulation. Taxol (which stabilizes microtubules) normalized the PD tubulin ratio and reduced alpha-synuclein oligomerization. A nexus exists between mitochondrial function, cytoskeleton homeostasis, and alpha-synuclein oligomerization. In our model, mitochondrial dysfunction triggers an increased free tubulin, which destabilizes the microtubular network and promotes alpha-synuclein oligomerization

Mitochondria at the Base of Neuronal Innate Immunity in Alzheimer’s and Parkinson’s Diseases

Mitochondria are exceptionally primed to play a key role in neuronal cell survival since they are involved in energy production and function as the metabolic center of cells. Several findings provide evidence for the role of mitochondria in neurodegeneration associated with Alzheimer’s and Parkinson’s diseases (AD and PD). Recent data highlight the role of mitochondrial proteins and mitochondrial reactive oxygen species in the intracellular signaling that regulates innate immunity and inflammation. In this chapter, we will discuss the relevance of the interplay between mitochondria and innate immunity, focusing on mitochondrial damage-associated molecular patterns (DAMPs) and how they can activate innate immunity and elicit AD and PD neurodegenerative process

A Knack to Know an Honest Man

Alzheimer’s disease (AD) is a multifactorial disorder with several target proteins contributing to its etiology. In search for multifunctional anti-AD drug candidates, taking into account that the acetylcholinesterase (AChE) and beta-amyloid (Aβ) aggregation are particularly important targets for inhibition, the tacrine and benzothiazole (BTA) moieties were conjugated with suitable linkers in a novel series of hybrids. The designed compounds (7a–7e) were synthesized and in vitro as well as in ex vivo evaluated for their capacity for the inhibition of acetylcholinesterase (AChE) and Aβ self-induced aggregation, and also for the protection of neuronal cells death (SHSY-5Y cells, AD and MCI cybrids). All the tacrine–BTA hybrids displayed high in vitro activities, namely with IC50 values in the low micromolar to sub-micromolar concentration range towards the inhibition of AChE, and high percentages of inhibition of the self-induced Aβ aggregation. Among them, compound 7a, with the shortest linker, presented the best inhibitory activity of AChE (IC50 = 0.34 μM), while the highest activity as anti-Aβ42 self-aggregation, was evidenced for compound 7b (61.3%, at 50 μM. The docking studies demonstrated that all compounds are able to interact with both catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. Our results show that compounds 7d and 7e improved cell viability in cells treated with Aβ42 peptide. Overall, these multi-targeted hybrid compounds appear as promising lead compounds for the treatment of Alzheimer’s disease

Tacrine-allyl/propargylcysteine-benzothiazole trihybrids as potential anti-Alzheimer's drug candidates

The authors acknowledge the Portuguese Fundação para a Ciência e Tecnologia (FCT) for the project UID/QUI/00100/2013, postdoctoral fellowships (RSK and KC). We also thank the doctoral fellowship from Erasmus Namaste program (AH).On continuing our research on new drug candidates for Alzheimer's disease (AD), we have designed, synthesized and evaluated a series of multifunctional trihybrid agents. The design strategy was based on the incorporation of a benzothiazole (BTA) moiety on a series of very recently reported bihybrids, resulting from the conjugation of a tacrine (TAC) with natural based moieties, namely S-allylcysteine (SAC) (garlic constituent) and S-propargylcysteine (SPRC). Thus, in addition to the acetylcholinesterase inhibition (AChEI) and anti-ROS capacity of the bihybrids (TAC-SAC/SPRC), the new trihybrids (TAC-SAC/SPRC-BTA) were endowed with 5-fold capacity for inhibition of the amyloid beta-peptide (Aβ) aggregation. The BTA moiety led also to considerable enhancement of the AChEI on the trihybrids, which molecular modeling suggested to be due to the simultaneous binding to the catalytic active site and peripheral anionic site of AChE. The trihybrids were also assessed for the MAO inhibition, but resulted in lower activity than expected, ascribed to the low accessibility of the propargyl groups to the enzyme active site. Finally, the effects of the compounds on the viability of neuroblastome cells stressedwith Aβ42 and H2O2 showed moderate cell protection. Overall, the performed studies illustrate the importance (and limitations) of enclosing several molecular scaffolds in one molecular entity to allow the modulation of multiple AD targets.PostprintPeer reviewe

Synthesis of esters derived from [4-(2-hydroxyethyl)-[1,2,3]triazol-1-yl]-2,3,4,6-tetra-O-acetyl-β-D-glucopyranose

The synthesis of six novel esters containing a triazole ring and an acetylated glucose residue are presentedFCT and FEDER, for National NMR Network (Bruker Avance II 400). We are also grateful for research grant VZ MSMT-0021627501, Czech Republi

Synthesis of esters derived from [4-(2-hydroxy-ethyl)-[1,2,3]triazol-1-YL-2,3,4,6-tetra-o-acetylglucopyranose

2,3,4-Tri-O-benzyl-alpha-D-methylglucoside was prepared and reacted with several acids: benzoic, phenylacetic, 2-(3-bromo-propoxy)-benzoic, acetylsalicylic and 4-(toluene-4-sulfonylamino)-benzoic. The products were isolated with low to fair yields and fully characterized by usual analytical techniquesFundação para a Ciência e Tecnologia and FEDER, for National NMR Network (Bruker Avance III 400). We are also grateful for research grant VZ MSMT-0021627501, Czech Republic

Impact of susceptibility-induced distortion correction on perfusion imaging by pCASL with a segmented 3D GRASE readout

Purpose: The consensus for the clinical implementation of arterial spin labeling (ASL) perfusion imaging recommends a segmented 3D Gradient and Spin-Echo (GRASE) readout for optimal signal-to-noise-ratio (SNR). The correction of the associated susceptibility-induced geometric distortions has been shown to improve diagnostic precision, but its impact on ASL data has not been systematically assessed and it is not consistently part of pre-processing pipelines. Here, we investigate the effects of susceptibility-induced distortion correction on perfusion imaging by pseudo-continuous ASL (pCASL) with a segmented 3D GRASE readout. Methods: Data acquired from 28 women using pCASL with 3D GRASE at 3T was analyzed using three pre-processing options: without distortion correction, with distortion correction, and with spatial smoothing (without distortion correction) matched to control for blurring effects induced by distortion correction. Maps of temporal SNR (tSNR) and relative perfusion were analyzed in eight regions-of-interest (ROIs) across the brain. Results: Distortion correction significantly affected tSNR and relative perfusion across the brain. Increases in tSNR were like those produced by matched spatial smoothing in most ROIs, indicating that they were likely due to blurring effects. However, that was not the case in the frontal and temporal lobes, where we also found increased relative perfusion with distortion correction even compared with matched spatial smoothing. These effects were found in both controls and patients, with no interactions with the participant group. Conclusion: Correction of susceptibility-induced distortions significantly impacts ASL perfusion imaging using a segmented 3D GRASE readout, and this step should therefore be considered in ASL pre-processing pipelines. This is of special importance in clinical studies, reporting perfusion across ROIs defined on relatively undistorted images and when conducting group analyses requiring the alignment of images across different subjects.info:eu-repo/semantics/publishedVersio

Projecto de educação pelos pares em escolas do Porto durante o ano lectivo 2009/2010

O Projecto Nacional de Educação pelos Pares, criado pela Fundação Portuguesa “A Comunidade Contra a Sida” visa a prevenção do VIH/SIDA e outros comportamentos de risco, através do desenvolvimento de projectos educativos implementados por voluntários universitários nos 7º e 8º anos de escolaridade. Estes estudantes universitários foram formados científica e pedagogicamente pela Fundação, e implementaram o projecto nacional de educação pelos pares com a supervisão de professores destacados para a FPCCS. Quando os alunos que iniciaram este projecto no 7º ano de escolaridade (12-13 anos) chegam ao 9º ano (14-15 anos), educam os seus pares dos 1º e 2º ciclos (6-11 anos) do ensino básico. A presente comunicação pretende discutir alguns dados recolhidos em seis escolas do porto envolvidas no Projecto Nacional de Educação pelos Pares, através de dois questionários de auto-resposta, designados "Sexualidade e SIDA", implementados no início do 1º e 2º anos de intervenção, que visam avaliar as necessidades de formação dos alunos nesta área. Os resultados obtidos mostraram que alguns alunos das escolas ignoram como prevenir a infecção pelo VIH e quais são os seus meios de transmissão. Por outro lado, têm a noção de que a infecção pelo VIH está associada a 'comportamentos de risco' não a 'grupos de risco'. A análise dos questionários do 8º ano evidenciou que os alunos gostaram mais de realizar dinâmicas de grupo, pelo impacto que tiveram na sua assertividade e na capacidade para reflectir sobre as consequências das suas escolhas e das decisões que tomam em relação ao seu comportamento sexual