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Title: | Extracellular vesicles improve GABAergic transmission in Huntington's disease iPSC-derived neurons | Authors: | Beatriz, Margarida Rodrigues, Ricardo J. Vilaça, Rita Egas, Conceição Pinheiro, Paulo S. Daley, George Q. Schlaeger, Thorsten M. Raimundo, Nuno Rego, A. Cristina Lopes, Carla |
Keywords: | Extracellular vesicles; Huntington’s disease; synaptogenesis; miRNAs | Issue Date: | 2023 | Publisher: | Ivyspring International Publisher | Project: | CENTRO-01-0145-FEDER-000012-Healthy Aging2020 POCI-01-0145-FEDER-029621 POCI-01-0145-FEDER- 022184 UIDB/04539/2020 Fundação Luso-Americana para o Desenvolvimento (FLAD) Life Science 2020 project CEECIND/00003/2018 CEECIND/00251/2021 |
Serial title, monograph or event: | Theranostics | Volume: | 13 | Issue: | 11 | Abstract: | Background: Extracellular vesicles (EVs) carry bioactive molecules associated with various biological processes, including miRNAs. In both Huntington’s disease (HD) models and human samples, altered expression of miRNAs involved in synapse regulation was reported. Recently, the use of EV cargo to reverse phenotypic alterations in disease models with synaptopathy as the end result of the pathophysiological cascade has become an interesting possibility. Methods: Here, we assessed the contribution of EVs to GABAergic synaptic alterations using a human HD model and studied the miRNA content of isolated EVs. Results: After differentiating human induced pluripotent stem cells into electrophysiologically active striatal-like GABAergic neurons, we found that HD-derived neurons displayed reduced density of inhibitory synapse markers and GABA receptor-mediated ionotropic signaling. Treatment with EVs secreted by control (CTR) fibroblasts reversed the deficits in GABAergic synaptic transmission and increased the density of inhibitory synapses in HD-derived neuron cultures, while EVs from HD-derived fibroblasts had the opposite effects on CTR-derived neurons. Moreover, analysis of miRNAs from purified EVs identified a set of differentially expressed miRNAs between manifest HD, premanifest, and CTR lines with predicted synaptic targets. Conclusion: The EV-mediated reversal of the abnormal GABAergic phenotype in HD-derived neurons reinforces the potential role of EV-miRNAs on synapse regulation. | URI: | https://hdl.handle.net/10316/114418 | ISSN: | 1838-7640 | DOI: | 10.7150/thno.81981 | Rights: | openAccess |
Appears in Collections: | FMUC Medicina - Artigos em Revistas Internacionais FCTUC Ciências da Vida - Artigos em Revistas Internacionais IIIUC - Artigos em Revistas Internacionais I&D CNC - Artigos em Revistas Internacionais |
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