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Título: | Anti-α-synuclein ASO delivered to monoamine neurons prevents α-synuclein accumulation in a Parkinson's disease-like mouse model and in monkeys |
Autor: | Alarcón-Arís, Diana CSIC; Pavia-Collado, Rubén CSIC ORCID; Miquel-Rio, Lluís CSIC ORCID; Coppola-Segovia, Valentín CSIC ORCID; Ferrés-Coy, Albert CSIC; Ruiz-Bronchal, Esther CSIC ORCID; Galofré, Mireia CSIC; Paz, Verónica CSIC ORCID; Campa, Leticia CSIC ORCID; Revilla, Raquel; Montefeltro, Andrés; Kordower, Jeffrey H.; Vila, M.; Artigas, Francesc CSIC ORCID; Bortolozzi, Analía CSIC ORCID | Palabras clave: | α-Synuclein Antisense oligonucleotides Axonal neurodegeneration Dopamine neurotransmission Mouse and monkey models Parkinson's disease |
Fecha de publicación: | 1-sep-2020 | Editor: | Elsevier | Citación: | EBioMedicine 59: 102944 (2020) | Resumen: | Background: Progressive neuronal death in monoaminergic nuclei and widespread accumulation of α-synuclein are neuropathological hallmarks of Parkinson's disease (PD). Given that α-synuclein may be an early mediator of the pathological cascade that ultimately leads to neurodegeneration, decreased α-synuclein synthesis will abate neurotoxicity if delivered to the key affected neurons. Methods: We used a non-viral gene therapy based on a new indatraline-conjugated antisense oligonucleotide (IND-ASO) to disrupt the α-synuclein mRNA transcription selectively in monoamine neurons of a PD-like mouse model and elderly nonhuman primates. Molecular, cell biology, histological, neurochemical and behavioral assays were performed. Findings: Intracerebroventricular and intranasal IND-ASO administration for four weeks in a mouse model with AAV-mediated wild-type human α-synuclein overexpression in dopamine neurons prevented the synthesis and accumulation of α-synuclein in the connected brain regions, improving dopamine neurotransmission. Likewise, the four-week IND-ASO treatment led to decreased levels of endogenous α-synuclein protein in the midbrain monoamine nuclei of nonhuman primates, which are affected early in PD. Conclusions: : The inhibition of α-synuclein production in dopamine neurons and its accumulation in cortical/striatal projection areas may alleviate the early deficits of dopamine function, showing the high translational value of antisense oligonucleotides as a disease modifying therapy for PD and related synucleinopathies. | Versión del editor: | http://dx.doi.org/10.1016/j.ebiom.2020.102944 | URI: | http://hdl.handle.net/10261/223696 | DOI: | 10.1016/j.ebiom.2020.102944 | Identificadores: | doi: 10.1016/j.ebiom.2020.102944 e-issn: 2352-3964 |
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