Extracellular vesicles improve GABAergic transmission in Huntington's disease iPSC-derived neurons

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

doi:10.7150/thno.81981

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Nanotheranostics 2024; 8(4): 442-457. [Abstract] [Full text] [PDF]

Nanotheranostics 2024; 8(4): 427-441. [Abstract] [Full text] [PDF]

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Theranostics 2023; 13(11):3707-3724. doi:10.7150/thno.81981 This issue Cite

Research Paper

Extracellular vesicles improve GABAergic transmission in Huntington's disease iPSC-derived neurons

Margarida Beatriz^1,2, Ricardo J. Rodrigues^1,2, Rita Vilaça^1,2, Conceição Egas^1,2,3, Paulo S. Pinheiro^1,4, George Q. Daley^5,6, Thorsten M. Schlaeger^5,6, Nuno Raimundo⁷, A. Cristina Rego^1,8✉, Carla Lopes^1,2,7✉

1. CNC - Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal.
2. IIIUC - Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal.
3. Biocant- Transfer Technology Association, Biocant Park, Cantanhede, Portugal.
4. Faculty of Sciences and Technology, Department of Life Sciences, University of Coimbra, 3000-456 Coimbra, Portugal.
5. Division of Pediatric Hematology/Oncology, Children's Hospital Boston, Boston, MA USA.
6. Harvard Stem Cell Institute, Boston, MA USA.
7. MIA - Multidisciplinary Institute of Ageing, University of Coimbra, Coimbra, Portugal.
8. FMUC - Faculty of Medicine, University of Coimbra, Coimbra, Portugal.

Citation:

Beatriz M, Rodrigues RJ, Vilaça R, Egas C, Pinheiro PS, Daley GQ, Schlaeger TM, Raimundo N, Rego AC, Lopes C. Extracellular vesicles improve GABAergic transmission in Huntington's disease iPSC-derived neurons. Theranostics 2023; 13(11):3707-3724. doi:10.7150/thno.81981. https://www.thno.org/v13p3707.htm

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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.

Keywords: Extracellular vesicles, Huntington's disease, synaptogenesis, miRNAs

Citation styles

APA

Beatriz, M., Rodrigues, R.J., Vilaça, R., Egas, C., Pinheiro, P.S., Daley, G.Q., Schlaeger, T.M., Raimundo, N., Rego, A.C., Lopes, C. (2023). Extracellular vesicles improve GABAergic transmission in Huntington's disease iPSC-derived neurons. Theranostics, 13(11), 3707-3724. https://doi.org/10.7150/thno.81981.

ACS

Beatriz, M.; Rodrigues, R.J.; Vilaça, R.; Egas, C.; Pinheiro, P.S.; Daley, G.Q.; Schlaeger, T.M.; Raimundo, N.; Rego, A.C.; Lopes, C. Extracellular vesicles improve GABAergic transmission in Huntington's disease iPSC-derived neurons. Theranostics 2023, 13 (11), 3707-3724. DOI: 10.7150/thno.81981.

NLM

CSE

Beatriz M, Rodrigues RJ, Vilaça R, Egas C, Pinheiro PS, Daley GQ, Schlaeger TM, Raimundo N, Rego AC, Lopes C. 2023. Extracellular vesicles improve GABAergic transmission in Huntington's disease iPSC-derived neurons. Theranostics. 13(11):3707-3724.

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