DOPAL derived alpha-synuclein oligomers impair synaptic vesicles physiological function

Parkinson's disease is a neurodegenerative disorder characterized by the death of dopaminergic neurons and by accumulation of alpha-synuclein (aS) aggregates in the surviving neurons. The dopamine catabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) is a highly reactive and toxic molecule that leads to aS oligomerization by covalent modifications to lysine residues. Here we show that DOPAL-induced aS oligomer formation in neurons is associated with damage of synaptic vesicles, and with alterations in the synaptic vesicles pools. To investigate the molecular mechanism that leads to synaptic impairment, we first aimed to characterize the biochemical and biophysical properties of the aS-DOPAL oligomers; heterogeneous ensembles of macromolecules able to permeabilise cholesterol-containing lipid membranes. aS-DOPAL oligomers can induce dopamine leak in an in vitro model of synaptic vesicles and in cellular models. The dopamine released, after conversion to DOPAL in the cytoplasm, could trigger a noxious cycle that further fuels the formation of aS-DOPAL oligomers, inducing neurodegeneration

The impact of COVID-19 on physical activity behaviour in Italian primary school children: a comparison before and during pandemic considering gender differences

Background: The World Health Organization stated an average of 60 min of Moderate to Vigorous Physical Activity (MVPA) that children should accumulate every day. Nevertheless physical inactivity is growing and, due to restrictions imposed during pandemic, PA levels of children might be more negatively affected. The study aimed to analyse the impact of COVID-19 on the PA of an Italian sample of primary school children by comparing it before and during COVID-19 considering gender differences. Methods: A pre-post analysis (October 2019–January 2021) was conducted using a randomized sample (N = 77) from the I-MOVE study settled in an Italian primary school. Both objective (Actigraph accelerometers) and selfreported (PAQ-c questionnaires) assessments of PA were performed. Changes were compared using T-Student and Chi-Square test. Gender differences were calculated using Anova. Results: Weekly and daily minutes time spent in MVPA significantly decreased respectively by − 30.59 ± 120.87 and − 15.32 ± 16.21 from before to during pandemic while the weekly time spent in sedentary behaviour increased (+ 1196.01 ± 381.49). PAQ-c scores followed the same negative trend (− 0.87 ± 0.72). Boys seem to have suffered more than girls from the imposed restrictions. Conclusion: These findings outline the need for strategies to promote PA and reduce sedentary behaviours in children to prevent COVID-19 restriction long-term effects

L’insertion professionnelle en Suisse ::quelle accessibilité ?

Se former, trouver et conserver un emploi constituent un défi pour tous les jeunes adultes. Pour les personnes présentant une déficience intellectuelle (DI), de nombreuses difficultés peuvent s’ajouter à celles normalement rencontrées, par exemple des formations professionnelles peu accessibles ou encore un environnement de travail inadapté. Pourtant lorsque des soutiens adéquats sont proposés, l’intégration professionnelle sur le premier marché de l’emploi est possible. De nombreux bénéfices sont alors observés tant pour les personnes elles-mêmes que pour les entreprises les employant.Sich auszubilden, eine Anstellung zu finden und zu bewahren ist eine grosse Herausforderung für alle jungen Erwachsenen. Für Menschen mit einer kognitiven Beeinträchtigung (im Text DI, déficience intellectuelle) kommen zu den allgemeinen Schwierigkeiten oft weitere Erschwernisse hinzu; etwa, wenn Berufsausbildungen nur schwer zugänglich oder Arbeitsumgebungen nicht angepasst sind. Jedoch ist mit einer geeigneten Unterstützung die berufliche Integration auf dem ersten Arbeitsmarkt durchaus möglich. Daraus ergeben sich sowohl für die betroffenen Personen wie auch für ihre Arbeitgeber viele Vorteile

DJ-1 is a copper chaperone acting on SOD1 activation.

Lack of oxidative stress control is a common and often prime feature observed in many neurodegenerative diseases. Both DJ-1 and SOD1, proteins involved in familial Parkinson disease and amyotrophic lateral sclerosis, respectively, play a protective role against oxidative stress. Impaired activity and modified expression of both proteins have been observed in different neurodegenerative diseases. A potential cooperative action of DJ-1 and SOD1 in the same oxidative stress response pathway may be suggested basedonacopper- mediatedinteractionbetweenthetwo proteins reported here. To investigate the mechanisms underlying the antioxidative function of DJ-1 in relation to SOD1 activity, we investigated the ability of DJ-1 to bind copper ions.Westructurally characterized a novel copper binding site involving Cys-106, and we investigated, using different techniques, the kinetics of DJ-1 binding to copper ions. The copper transfer between the two proteins was also examined using both fluorescence spectroscopy and specific biochemical assays for SOD1 activity. The structural and functional analysis of the novel DJ-1 copper binding site led us to identify a putative role for DJ-1 as a copper chaperone. Alteration of the coordination geometry of the copper ion in DJ-1 may be correlated to the physiological role of the protein, to a potential failure in metal transfer to SOD1, and to successive implications in neurodegenerative etiopathogenesis

Dopamine-derived Quinones Affect the Structure of the Redox Sensor DJ-1 through Modifications at Cys-106 andCys-53

The physiological role of DJ-1, a protein involved in familial Parkinson disease is still controversial. One of the hypotheses proposed indicates a sensor role for oxidative stress, through oxidation of a conserved cysteine residue (Cys-106). The association of DJ-1 mutations with Parkinson disease suggests a loss of function, specific to dopaminergic neurons. Under oxidative conditions, highly reactive dopamine quinones (DAQs) can be produced, which can modify cysteine residues. In cellular models, DJ-1 was found covalently modified by dopamine. We analyzed the structural modifications induced on human DJ-1 by DAQs in vitro. We described the structural perturbations induced byDAQadduct formation on each of the three cysteine residues of DJ-1 using specific mutants. Cys-53 is the most reactive residue and forms a covalent dimer also in SH-SY5Y DJ-1- transfected cells, but modification of Cys-106 induces the most severe structural perturbations; Cys-46 is not reactive. The relevance of these covalent modifications to the several functions ascribed to DJ-1 is discussed in the context of the cell response to a dopamine-derived oxidative insult

Over-Under Triage nell’attivazione del Trauma Team: un’analisi retrospettiva nella ASST Monza

Introduction: Meeting the literature standards during the triage process of trauma victims, allows to make optimal use of the resources available in Trauma Centers and defines their level of quality and efficiency. Otherwise, it may occur over or under-triage. Up to now, in the reality under study and in the national literature, there wasn’t any available data about efficiency and effectiveness in the triage of traumatic patients, therefore the primary objective of this study is to evaluate the over and under-triage rate in activating Trauma Team (TT) in the ASST of Monza-San Gerardo Hospital. Method: The study design is retrospective monocentric observational. Results: During the analysis, the TT-activation in ASST of Monza-San Gerardo Hospital produced an over-triage of 62,9% and an under-triage of 1,7% for the same year. Discussion: The use of TT-activation algorithm is the first step of the entire care process of the trauma victim. This tool should guarantee the right balance between high sensitivity (under-triage → 0, accepting the risk of high over-triage rate) and high specificity (minimum over-triage rate with the possibility of higher under-triage). However, there is no sharing of these algorithms as they are inhomogeneous in the different realities; for example, the definition of major trauma, of TT and of its composition is still uneven. Conclusion: This study measured the over and under-triage rate related to the TT activation in the ASST of Monza. It is therefore advisable to monitor those rates periodically, as possible indicators of quality of assistance and to pursue the mission of increasing efficiency as well as effectiveness.Introduzione: Il rispetto degli standard presenti in letteratura durante il triage di persone vittima di trauma, permette di sfruttare in modo ottimale le risorse di cui dispongono i Trauma Center e ne definisce il livello di qualità ed efficienza. In caso contrario si può assistere ad over o under-triage. Fino a questo momento, nella realtà oggetto di studio e nella letteratura nazionale, non era disponibile alcuna misurazione di efficienza ed efficacia circa il relativo triage del paziente traumatico; pertanto l’obiettivo primario è ottenere dati relativi alle percentuali di over-triage e under-triage circa l’attivazione del Trauma Team (TT) nell’ASST di Monza-Ospedale San Gerardo. Metodo: Il disegno di studio è osservazionale retrospettivo monocentrico. Risultati: Nell’Ospedale San Gerardo, nel periodo esaminato, si è prodotto un over-triage del 62,9% ed un under-triage, relativo al medesimo anno, dell’1,7%. Discussione: Utilizzare un algoritmo decisionale di attivazione del TT è alla base dell’intero processo assistenziale della persona vittima di trauma. Questo strumento dovrebbe riportare il giusto compromesso tra sensibilità elevata (under-triage → 0, accettando il rischio di avere un over-triage elevato) e specificità elevata (over-triage minimo ma con possibilità di creare un più elevato under-triage). Non vi è tuttavia condivisione di tali algoritmi che risultano disomogenei nelle diverse realtà come è ancora disomogenea la definizione di trauma maggiore, del TT e della sua composizione. Conclusioni: Abbiamo misurato le percentuali di over e under triage relative all’attivazione del TT dell’ASST di Monza. Ci si aspetta di poterle monitorarle periodicamente, quali possibili indicatori di qualità d’assistenza al cittadino, ponendosi come mission, al pari dell’efficacia, di incrementare l’efficienza.&nbsp

HOW A METABOLITE OF DOPAMINE CAN TRANSFORM ALPHA­SYNUCLEIN IN AN ENDOTOXIN

The dopamine metabolite 3,4­dihydroxyphenylacetaldehyde (DOPAL) is highly reactive aldehyde of great interest in neurodegeneration. DOPAL is typically processed by the enzyme aldehyde dehydrogenase that is able to detoxify neurons by conversion of the DOPAL to a non­toxic molecule, i.e. 3,4­dihydroxyphenylacetic acid. The toxicity ascribed to DOPAL acquires particular interest for Parkinson’s disease (PD), being the dopaminergic neurons primary affected in the disorder. In this frame, it was reported that DOPAL is accumulated in neurons in parkinsonian brains where it can chemically modify alpha­synuclein (aS), a protein strongly associated to familial and sporadic forms of PD. aS is a natively unfolded protein prone to form aggregates, which are found in parkinsonian brains. The goal of our study is the characterization of the synergistic toxic effect exerted by DOPAL and aS in PD, due to the formation of aS/DOPAL oligomeric species. To this aim, we used a broad range of biophysical and biochemical techniques to characterize the chemical modification of aS generated by the reaction with DOPAL and the heterogeneous ensemble of resulting oligomeric aggregated species. aS is modified by DOPAL mainly at lysine residues as verified by mass spectrometry and NMR. The aS modifications lead to the formation of oligomers, which were characterize by transmission electron microscopy, dynamic light scattering and atomic force microscopy. These DOPAL dependent aS oligomers can permeabilize artificial lipid membranes, when they contain cholesterol, and induce ions and dopamine leakage. The formation and the toxicity of these aS oligomers have been evaluate also in a cellular model, i.e. the dopaminergic neuroblastoma cell line BE(2)­M17