Anti-α-synuclein ASO delivered to monoamine neurons prevents α-synuclein accumulation in a Parkinson's disease-like mouse model and in monkeys
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, decrease...
| Autores: | , , , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2020 |
| País: | España |
| Institución: | Consejo Superior de Investigaciones Científicas (CSIC) |
| Repositorio: | DIGITAL.CSIC. Repositorio Institucional del CSIC |
| OAI Identifier: | oai:digital.csic.es:10261/223696 |
| Acceso en línea: | http://hdl.handle.net/10261/223696 |
| Access Level: | acceso abierto |
| Palabra clave: | α-Synuclein Antisense oligonucleotides Axonal neurodegeneration Dopamine neurotransmission Mouse and monkey models Parkinson's disease |
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Anti-α-synuclein ASO delivered to monoamine neurons prevents α-synuclein accumulation in a Parkinson's disease-like mouse model and in monkeysAlarcón-Arís, DianaPavia-Collado, RubénMiquel-Rio, LluísCoppola-Segovia, ValentínFerrés-Coy, AlbertRuiz-Bronchal, EstherGalofré, MireiaPaz, VerónicaCampa, LeticiaRevilla, RaquelMontefeltro, AndrésKordower, Jeffrey H.Vila, M.Artigas, FrancescBortolozzi, Analíaα-SynucleinAntisense oligonucleotidesAxonal neurodegenerationDopamine neurotransmissionMouse and monkey modelsParkinson's diseaseBackground: 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.Grants SAF2016-75797-R, RTC-2014-2812-1 and RTC-2015-3309-1, Ministry of Economy and Competitiveness (MINECO) and European Regional Development Fund (ERDF), UE; Grant ID 9238, Michael J. Fox Foundation; and Centres for Networked Biomedical Research on Mental Health (CIBERSAM), and on Neurodegenerative Diseases (CIBERNED).ElsevierMinisterio de Economía y Competitividad (España)European CommissionMichael J. Fox Foundation for Parkinson's ResearchCentro de Investigación Biomédica en Red Salud Mental (España)Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2020202020202020info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/223696reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2016-75797-Rinfo:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/RTC-2014-2812-1info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/RTC-2015-3309-1http://dx.doi.org/10.1016/j.ebiom.2020.102944Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2236962026-05-22T06:33:51Z |
| dc.title.none.fl_str_mv |
Anti-α-synuclein ASO delivered to monoamine neurons prevents α-synuclein accumulation in a Parkinson's disease-like mouse model and in monkeys |
| title |
Anti-α-synuclein ASO delivered to monoamine neurons prevents α-synuclein accumulation in a Parkinson's disease-like mouse model and in monkeys |
| spellingShingle |
Anti-α-synuclein ASO delivered to monoamine neurons prevents α-synuclein accumulation in a Parkinson's disease-like mouse model and in monkeys Alarcón-Arís, Diana α-Synuclein Antisense oligonucleotides Axonal neurodegeneration Dopamine neurotransmission Mouse and monkey models Parkinson's disease |
| title_short |
Anti-α-synuclein ASO delivered to monoamine neurons prevents α-synuclein accumulation in a Parkinson's disease-like mouse model and in monkeys |
| title_full |
Anti-α-synuclein ASO delivered to monoamine neurons prevents α-synuclein accumulation in a Parkinson's disease-like mouse model and in monkeys |
| title_fullStr |
Anti-α-synuclein ASO delivered to monoamine neurons prevents α-synuclein accumulation in a Parkinson's disease-like mouse model and in monkeys |
| title_full_unstemmed |
Anti-α-synuclein ASO delivered to monoamine neurons prevents α-synuclein accumulation in a Parkinson's disease-like mouse model and in monkeys |
| title_sort |
Anti-α-synuclein ASO delivered to monoamine neurons prevents α-synuclein accumulation in a Parkinson's disease-like mouse model and in monkeys |
| dc.creator.none.fl_str_mv |
Alarcón-Arís, Diana Pavia-Collado, Rubén Miquel-Rio, Lluís Coppola-Segovia, Valentín Ferrés-Coy, Albert Ruiz-Bronchal, Esther Galofré, Mireia Paz, Verónica Campa, Leticia Revilla, Raquel Montefeltro, Andrés Kordower, Jeffrey H. Vila, M. Artigas, Francesc Bortolozzi, Analía |
| author |
Alarcón-Arís, Diana |
| author_facet |
Alarcón-Arís, Diana Pavia-Collado, Rubén Miquel-Rio, Lluís Coppola-Segovia, Valentín Ferrés-Coy, Albert Ruiz-Bronchal, Esther Galofré, Mireia Paz, Verónica Campa, Leticia Revilla, Raquel Montefeltro, Andrés Kordower, Jeffrey H. Vila, M. Artigas, Francesc Bortolozzi, Analía |
| author_role |
author |
| author2 |
Pavia-Collado, Rubén Miquel-Rio, Lluís Coppola-Segovia, Valentín Ferrés-Coy, Albert Ruiz-Bronchal, Esther Galofré, Mireia Paz, Verónica Campa, Leticia Revilla, Raquel Montefeltro, Andrés Kordower, Jeffrey H. Vila, M. Artigas, Francesc Bortolozzi, Analía |
| author2_role |
author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Ministerio de Economía y Competitividad (España) European Commission Michael J. Fox Foundation for Parkinson's Research Centro de Investigación Biomédica en Red Salud Mental (España) Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España) Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72] |
| dc.subject.none.fl_str_mv |
α-Synuclein Antisense oligonucleotides Axonal neurodegeneration Dopamine neurotransmission Mouse and monkey models Parkinson's disease |
| topic |
α-Synuclein Antisense oligonucleotides Axonal neurodegeneration Dopamine neurotransmission Mouse and monkey models Parkinson's disease |
| description |
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. |
| publishDate |
2020 |
| dc.date.none.fl_str_mv |
2020 2020 2020 2020 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article http://purl.org/coar/resource_type/c_6501 Publisher's version info:eu-repo/semantics/publishedVersion |
| format |
article |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10261/223696 |
| url |
http://hdl.handle.net/10261/223696 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
#PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2016-75797-R info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/RTC-2014-2812-1 info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/RTC-2015-3309-1 http://dx.doi.org/10.1016/j.ebiom.2020.102944 Sí |
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info:eu-repo/semantics/openAccess |
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openAccess |
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Elsevier |
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Elsevier |
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reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC instname:Consejo Superior de Investigaciones Científicas (CSIC) |
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Consejo Superior de Investigaciones Científicas (CSIC) |
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DIGITAL.CSIC. Repositorio Institucional del CSIC |
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