Selective suppression of α-Synuclein in monoaminergic neurons of mice by intranasal delivery of targeted small interfering RNA or antisense oligonucleotides: Potential therapy for Parkinson's disease

Póster presentado en: ACNP (American College of Neuropsychopharmacology) 52nd Annual Conference, celebrada del 8 al 12 de diciembre de 2013 en Hollywood, Florida (Estados Unidos)Abstract publicado en: Neuropsychopharmacology 38:S419-S420 (2013). ISSN: 0893-133X. eISSN: 1740-634X. DOI:10.1038/npp.2013.280α-Synuclein (α-Syn) appears to play a crucial role in the pathogenesis of several neurodegenerative disorders including Parkinson's disease (PD). The brains of Parkinson patients typically contain insoluble intracellular protein inclusions called Lewy bodies. Increased neuronal α-Syn levels represent a major component of Lewy bodies and therefore, the suppression of α-Syn expression provides a valid therapeutic target for PD. The goal of this study was to assess the ability of various small interfering RNA (siRNA) and antisense oligonucleotide (ASO) sequences directed against α-Syn to downregulate endogenous or overexpressed α-Syn mRNA levels in BE-M17 neuroblastoma cells. Moreover, we evaluated the feasibility of reducing α-Syn expression selectively in PD-vulnerable brain areas including substantia nigra pars compacta (SNc), ventral tegmental area (VTA), locus coeruleus (LC) and dorsal raphe nucleus (DR) of mice after the internalization of conjugated siRNA/ASO molecules into monoamine neurons following intranasal administration. Conclusions: These results set the stage for the testing of these molecules as potential disease-modifying agents in neurotoxin-based and genetic models of PD linked to pathogenic increases in α-Syn. In this study we have characterized conjugated siRNA and ASO molecules that actively reduce endogenous α-Syn expression in vivo using the intranasal route to deliver directly siRNA/ASO into the brainPeer Reviewe

Conséquences de la dénervation dopaminergique chez la rat lésé à la 6-OHDA sur les structures situées en aval des lésions (analyse du noyau subthalamique et de la zona incerta)

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Consommation de 3-méthylméthcathinone : mise en garde sur le risque de modifications électrocardiographiques ! À propos d’un cas

International audienc

Pathogenic lysosomal depletion in Parkinson´s disease

10 páginas, 7 figuras -- PAGS nros. 12535-12544Mounting evidence suggests a role for autophagy dysregulation in Parkinson's disease (PD). The bulk degradation of cytoplasmic proteins (including α-synuclein) and organelles (such as mitochondria) is mediated by macroautophagy, which involves the sequestration of cytosolic components into autophagosomes (AP) and its delivery to lysosomes. Accumulation of AP occurs in postmortem brain samples from PD patients, which has been widely attributed to an induction of autophagy. However, the cause and pathogenic significance of these changes remain unknown. Here we found in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of PD that AP accumulation and dopaminergic cell death are preceded by a marked decrease in the amount of lysosomes within dopaminergic neurons. Lysosomal depletion was secondary to the abnormal permeabilization of lysosomal membranes induced by increased mitochondrial-derived reactive oxygen species. Lysosomal permeabilization resulted in a defective clearance and subsequent accumulation of undegraded AP and contributed directly to neurodegeneration by the ectopic release of lysosomal proteases into the cytosol. Lysosomal breakdown and AP accumulation also occurred in PD brain samples, where Lewy bodies were strongly immunoreactive for AP markers. Induction of lysosomal biogenesis by genetic or pharmacological activation of lysosomal transcription factor EB restored lysosomal levels, increased AP clearance and attenuated 1-methyl-4-phenylpyridinium-induced cell death. Similarly, the autophagy-enhancer compound rapamycin attenuated PD-related dopaminergic neurodegeneration, both in vitro and in vivo, by restoring lysosomal levels. Our results indicate that AP accumulation in PD results from defective lysosomal-mediated AP clearance secondary to lysosomal depletion. Restoration of lysosomal levels and function may thus represent a novel neuroprotective strategy in PDThis work was supported by European Commission Marie Curie Excellence Grant and Marie Curie International Reintegration Grant (M.V.), Fundació la Caixa, Spain (M.V., P.B.), Fondo de Investigación Sanitaria-Instituto de Salud Carlos III, Spain (M.V.), Ministerio de Ciencia e Innovación (MICINN), Spain (P.B.), Comunidad de Madrid, Spain (P.B.), and Ramón y Cajal (C.P., P.B.) and Formación del Profesorado Universitario programmes (N.R.-M.) from MICINN, Spain. B.D. is the recipient of a fellowship award from the Foundation Bettencourt-Schueller (France)Peer reviewe

Implication de l’addictovigilance dans un service d’urgence pour la détection et le recueil des cas d’abus et de dépendance : bilan de 3 ans d’expérience

International audienceDue to the increase of hospitalization at emergency department (ED) related to psychoactive substances use (PSU), the addictovigilance center of Montpellier has been integrated into the URGEIM program for the detection of iatrogenic events at the ED. The objective of the present work was to analyze spontaneous reports (SR) collected via the URGEIM program.METHODS:Analysis of spontaneous reports related to PSU at the ED of the Montpellier University Hospital, collected through the URGEIM program, between January 2014 and December 2016.RESULTS:During the study period, 160 SR were collected through the URGEIM program on 1118 SR collected by the Addictovigilance center over the period: 40SR/342 in 2014, 46 SR/303 in 2015 and 74 SR/473 in 2016. Most patients were male (70%) and the mean age at admission was 33 years old. A total of 240 psychoactive substances were identified with 160 illicit substances (66.6%) [cocaine 38.1%, cannabis 30.6%] and 80 medications (33.3%) [buprenorphine 22.5%, benzodiazepines 20% and methadone 18.8%]. Mental and behavioral disorders (20.0%), general health problems associated with substance use (17.5%), cardiovascular diseases (13.1%) and infectious diseases (12.5%) were the main reported effects. The duration of emergency stay was inferior to 12hours in 63.1% of cases and greater than 24hours in 12.5% of cases. In 69.4% of cases, the event was considered as serious. The outcome was unknown for 6.9% of patients.CONCLUSION:The number of SR from ED has increased over the study period, with the notification of serious and worrying cases, and the possibility of setting up actions. The deployment of addictovigilance within clinical services is a significant factor for notification and quality of care