Intracerebral Administration of a Ligand-ASO Conjugate Selectively Reduces α-Synuclein Accumulation in Monoamine Neurons of Double Mutant Human A30P*A53T*α-Synuclein Transgenic Mice

α-Synuclein (α-Syn) protein is involved in the pathogenesis of Parkinson’s disease (PD). Point mutations and multiplications of the α-Syn, which encodes the SNCA gene, are correlated with early-onset PD, therefore the reduction in a-Syn synthesis could be a potential therapy for PD if delivered to t...

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Autores: Pavia-Collado, Rubén, Cóppola-Segovia, Valentín, Miquel-Rio, Lluis, Alarcón-Arís, Diana, Rodríguez-Aller, Raquel, Torres López, María, Bortolozzi, Analia
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Universidad de Sevilla (US)
Repositorio:idUS. Depósito de Investigación de la Universidad de Sevilla
OAI Identifier:oai:idus.us.es:11441/149281
Acceso en línea:https://hdl.handle.net/11441/149281
https://doi.org/10.3390/ijms22062939
Access Level:acceso abierto
Palabra clave:α-synuclein
Antisense oligonucleotide
Dopamine neurotransmission
Double mutant A30P*A53T*
Motor deficits
Parkinson’s disease
Transgenic mouse model
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spelling Intracerebral Administration of a Ligand-ASO Conjugate Selectively Reduces α-Synuclein Accumulation in Monoamine Neurons of Double Mutant Human A30P*A53T*α-Synuclein Transgenic MicePavia-Collado, RubénCóppola-Segovia, ValentínMiquel-Rio, LluisAlarcón-Arís, DianaRodríguez-Aller, RaquelTorres López, MaríaBortolozzi, Analiaα-synucleinAntisense oligonucleotideDopamine neurotransmissionDouble mutant A30P*A53T*Motor deficitsParkinson’s diseaseTransgenic mouse modelα-Synuclein (α-Syn) protein is involved in the pathogenesis of Parkinson’s disease (PD). Point mutations and multiplications of the α-Syn, which encodes the SNCA gene, are correlated with early-onset PD, therefore the reduction in a-Syn synthesis could be a potential therapy for PD if delivered to the key affected neurons. Several experimental strategies for PD have been developed in recent years using oligonucleotide therapeutics. However, some of them have failed or even caused neuronal toxicity. One limiting step in the success of oligonucleotide-based therapeutics is their delivery to the brain compartment, and once there, to selected neuronal populations. Previously, we developed an indatraline-conjugated antisense oligonucleotide (IND-1233-ASO), that selectively reduces α-Syn synthesis in midbrain monoamine neurons of mice, and nonhuman primates. Here, we extended these observations using a transgenic male mouse strain carrying both A30P and A53T mutant human α-Syn (A30P*A53T*α-Syn). We found that A30P*A53T*α-Syn mice at 4–5 months of age showed 3.5-fold increases in human α-Syn expression in dopamine (DA) and norepinephrine (NE) neurons of the substantia nigra pars compacta (SNc) and locus coeruleus (LC), respectively, compared with mouse α-Syn levels. In parallel, transgenic mice exhibited altered nigrostriatal DA neurotransmission, motor alterations, and an anxiety-like phenotype. Intracerebroventricular IND-1233-ASO administration (100 µg/day, 28 days) prevented the α-Syn synthesis and accumulation in the SNc and LC, and recovered DA neurotransmission, although it did not reverse the behavioral phenotype. Therefore, the present therapeutic strategy based on a conjugated ASO could be used for the selective inhibition of α-Syn expression in PD-vulnerable monoamine neurons, showing the benefit of the optimization of ASO molecules as a disease modifying therapy for PD and related α-synucleinopathies.SAF2016-75797-RPID2019-105136RB-100Center for Networked Biomedical Research on Mental Health (CIBERSAM)Unión Europea, European Regional Development Fund (ERDF)Ministerio de Economía y Competitividad (MINECO)RetosColaboracion Subprogram RTC-2015-3309-1MDPIFisiología Médica y Biofísica2021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttps://hdl.handle.net/11441/149281https://doi.org/10.3390/ijms22062939reponame:idUS. Depósito de Investigación de la Universidad de Sevillainstname:Universidad de Sevilla (US)InglésInternational Journal of Molecular Sciences, 22 (6), 1-20.info:eu-repo/semantics/openAccessoai:idus.us.es:11441/1492812026-06-17T12:51:07Z
dc.title.none.fl_str_mv Intracerebral Administration of a Ligand-ASO Conjugate Selectively Reduces α-Synuclein Accumulation in Monoamine Neurons of Double Mutant Human A30P*A53T*α-Synuclein Transgenic Mice
title Intracerebral Administration of a Ligand-ASO Conjugate Selectively Reduces α-Synuclein Accumulation in Monoamine Neurons of Double Mutant Human A30P*A53T*α-Synuclein Transgenic Mice
spellingShingle Intracerebral Administration of a Ligand-ASO Conjugate Selectively Reduces α-Synuclein Accumulation in Monoamine Neurons of Double Mutant Human A30P*A53T*α-Synuclein Transgenic Mice
Pavia-Collado, Rubén
α-synuclein
Antisense oligonucleotide
Dopamine neurotransmission
Double mutant A30P*A53T*
Motor deficits
Parkinson’s disease
Transgenic mouse model
title_short Intracerebral Administration of a Ligand-ASO Conjugate Selectively Reduces α-Synuclein Accumulation in Monoamine Neurons of Double Mutant Human A30P*A53T*α-Synuclein Transgenic Mice
title_full Intracerebral Administration of a Ligand-ASO Conjugate Selectively Reduces α-Synuclein Accumulation in Monoamine Neurons of Double Mutant Human A30P*A53T*α-Synuclein Transgenic Mice
title_fullStr Intracerebral Administration of a Ligand-ASO Conjugate Selectively Reduces α-Synuclein Accumulation in Monoamine Neurons of Double Mutant Human A30P*A53T*α-Synuclein Transgenic Mice
title_full_unstemmed Intracerebral Administration of a Ligand-ASO Conjugate Selectively Reduces α-Synuclein Accumulation in Monoamine Neurons of Double Mutant Human A30P*A53T*α-Synuclein Transgenic Mice
title_sort Intracerebral Administration of a Ligand-ASO Conjugate Selectively Reduces α-Synuclein Accumulation in Monoamine Neurons of Double Mutant Human A30P*A53T*α-Synuclein Transgenic Mice
dc.creator.none.fl_str_mv Pavia-Collado, Rubén
Cóppola-Segovia, Valentín
Miquel-Rio, Lluis
Alarcón-Arís, Diana
Rodríguez-Aller, Raquel
Torres López, María
Bortolozzi, Analia
author Pavia-Collado, Rubén
author_facet Pavia-Collado, Rubén
Cóppola-Segovia, Valentín
Miquel-Rio, Lluis
Alarcón-Arís, Diana
Rodríguez-Aller, Raquel
Torres López, María
Bortolozzi, Analia
author_role author
author2 Cóppola-Segovia, Valentín
Miquel-Rio, Lluis
Alarcón-Arís, Diana
Rodríguez-Aller, Raquel
Torres López, María
Bortolozzi, Analia
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv Fisiología Médica y Biofísica
dc.subject.none.fl_str_mv α-synuclein
Antisense oligonucleotide
Dopamine neurotransmission
Double mutant A30P*A53T*
Motor deficits
Parkinson’s disease
Transgenic mouse model
topic α-synuclein
Antisense oligonucleotide
Dopamine neurotransmission
Double mutant A30P*A53T*
Motor deficits
Parkinson’s disease
Transgenic mouse model
description α-Synuclein (α-Syn) protein is involved in the pathogenesis of Parkinson’s disease (PD). Point mutations and multiplications of the α-Syn, which encodes the SNCA gene, are correlated with early-onset PD, therefore the reduction in a-Syn synthesis could be a potential therapy for PD if delivered to the key affected neurons. Several experimental strategies for PD have been developed in recent years using oligonucleotide therapeutics. However, some of them have failed or even caused neuronal toxicity. One limiting step in the success of oligonucleotide-based therapeutics is their delivery to the brain compartment, and once there, to selected neuronal populations. Previously, we developed an indatraline-conjugated antisense oligonucleotide (IND-1233-ASO), that selectively reduces α-Syn synthesis in midbrain monoamine neurons of mice, and nonhuman primates. Here, we extended these observations using a transgenic male mouse strain carrying both A30P and A53T mutant human α-Syn (A30P*A53T*α-Syn). We found that A30P*A53T*α-Syn mice at 4–5 months of age showed 3.5-fold increases in human α-Syn expression in dopamine (DA) and norepinephrine (NE) neurons of the substantia nigra pars compacta (SNc) and locus coeruleus (LC), respectively, compared with mouse α-Syn levels. In parallel, transgenic mice exhibited altered nigrostriatal DA neurotransmission, motor alterations, and an anxiety-like phenotype. Intracerebroventricular IND-1233-ASO administration (100 µg/day, 28 days) prevented the α-Syn synthesis and accumulation in the SNc and LC, and recovered DA neurotransmission, although it did not reverse the behavioral phenotype. Therefore, the present therapeutic strategy based on a conjugated ASO could be used for the selective inhibition of α-Syn expression in PD-vulnerable monoamine neurons, showing the benefit of the optimization of ASO molecules as a disease modifying therapy for PD and related α-synucleinopathies.
publishDate 2021
dc.date.none.fl_str_mv 2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/11441/149281
https://doi.org/10.3390/ijms22062939
url https://hdl.handle.net/11441/149281
https://doi.org/10.3390/ijms22062939
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv International Journal of Molecular Sciences, 22 (6), 1-20.
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:idUS. Depósito de Investigación de la Universidad de Sevilla
instname:Universidad de Sevilla (US)
instname_str Universidad de Sevilla (US)
reponame_str idUS. Depósito de Investigación de la Universidad de Sevilla
collection idUS. Depósito de Investigación de la Universidad de Sevilla
repository.name.fl_str_mv
repository.mail.fl_str_mv
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