MicroRNA-124 loaded nanoparticles enhance brain repair in Parkinson's disease.
Modulation of the subventricular zone (SVZ) neurogenic niche can enhance brain repair in several disorders including Parkinson's disease (PD). Herein, we used biocompatible and traceable polymeric nanoparticles (NPs) containing perfluoro-1,5-crown ether (PFCE) and coated with protamine sulfate to complex microRNA-124 (miR-124), a neuronal fate determinant. The ability of NPs to efficiently deliver miR-124 and prompt SVZ neurogenesis and brain repair in PD was evaluated. In vitro, miR-124 NPs were efficiently internalized by neural stem/progenitors cells and neuroblasts and promoted their neuronal commitment and maturation. The expression of Sox9 and Jagged1, two miR-124 targets and stemness-related genes, were also decreased upon miR-124 NP treatment. In vivo, the intracerebral administration of miR-124 NPs increased the number of migrating neuroblasts that reached the granule cell layer of the olfactory bulb, both in healthy and in a 6-hydroxydopamine (6-OHDA) mouse model for PD. MiR-124 NPs were also able to induce migration of neurons into the lesioned striatum of 6-OHDA-treated mice. Most importantly, miR-124 NPs proved to ameliorate motor symptoms of 6-OHDA mice, monitored by the apomorphine-induced rotation test. Altogether, we provide clear evidences to support the use of miR-124 NPs as a new therapeutic approach to boost endogenous brain repair mechanisms in a setting of neurodegeneration.
Health Sciences Research Centre, Faculty of Health Sciences, University of Beira Interior, 6201-506 Covilhã, Portugal.
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Saraiva
CNC-Center for Neuroscience and Cell Biology, 3004-504 Coimbra, Portugal; Biocant - Center of Innovation in Biotechnology, 3060-197 Cantanhede, Portugal.
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Paiva
Health Sciences Research Centre, Faculty of Health Sciences, University of Beira Interior, 6201-506 Covilhã, Portugal.
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Santos
CNC-Center for Neuroscience and Cell Biology, 3004-504 Coimbra, Portugal; Biocant - Center of Innovation in Biotechnology, 3060-197 Cantanhede, Portugal; Institute for Interdisciplinary Research, University of Coimbra (IIIUC), 3030-789 Coimbra, Portugal.
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Ferreira
Health Sciences Research Centre, Faculty of Health Sciences, University of Beira Interior, 6201-506 Covilhã, Portugal. Electronic address: libernardino@fcsaude.ubi.pt.
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Bernardino
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D000072100:Jagged-1 Protein / Q000235:genetics / Q000378:metabolism; D020547:Lateral Ventricles / Q000166:cytology; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000008:administration & dosage* / Q000627:therapeutic use; D053758:Nanoparticles / Q000008:administration & dosage* / Q000627:therapeutic use; D058953:Neural Stem Cells / Q000187:drug effects; D055495:Neurogenesis / Q000187:drug effects; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy*; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism
C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D035683:MicroRNAs; C540079:Mirn124 microRNA, mouse; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; D016627:Oxidopamine
MiR-124; Nanoparticles; Neural stem cells; Neurogenesis; Parkinson's disease