SNCA genetic lowering reveals differential cognitive function of alpha-synuclein dependent on sex

Antisense oligonucleotide (ASO) therapy for neurological disease has been successful in clinical settings and its potential has generated hope for Alzheimer's disease (AD). We previously described that ablating SNCA encoding for alpha-synuclein (alpha Syn) in a mouse model of AD was beneficial....

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Autores: Brown, Jennifer L., Hart, Damyan W., Boyle, Gabriel E., Brown, Taylor G., LaCroix, Michael, Baraibar Sierra, Andrés Mateo, Pelzel, Ross, Kim, Minwoo, Sherman, Mathew A., Boes, Samuel, Sung, Michelle, Cole, Tracy, Lee, Michael K., Araque, Alfonso, Lesne, Sylvain E.
Tipo de recurso: artículo
Fecha de publicación:2022
País:España
Institución:Universidad del País Vasco
Repositorio:Addi. Archivo Digital para la Docencia y la Investigación
OAI Identifier:oai:addi.ehu.eus:10810/59487
Acceso en línea:http://hdl.handle.net/10810/59487
Access Level:acceso abierto
Palabra clave:alpha-synuclein
spatial memory
sex
antisense oligonucleotide
synucleinopathy
Alzheimer's disease
early growth response 1
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spelling SNCA genetic lowering reveals differential cognitive function of alpha-synuclein dependent on sexBrown, Jennifer L.Hart, Damyan W.Boyle, Gabriel E.Brown, Taylor G.LaCroix, MichaelBaraibar Sierra, Andrés MateoPelzel, RossKim, MinwooSherman, Mathew A.Boes, SamuelSung, MichelleCole, TracyLee, Michael K.Araque, AlfonsoLesne, Sylvain E.alpha-synucleinspatial memorysexantisense oligonucleotidesynucleinopathyAlzheimer's diseaseearly growth response 1Antisense oligonucleotide (ASO) therapy for neurological disease has been successful in clinical settings and its potential has generated hope for Alzheimer's disease (AD). We previously described that ablating SNCA encoding for alpha-synuclein (alpha Syn) in a mouse model of AD was beneficial. Here, we sought to demonstrate whether transient reduction of alpha Syn expression using ASO(SNCA) could be therapeutic in a mouse model of AD. The efficacy of the ASO(SNCA) was measured via immunocytochemistry, RT-qPCR and western blotting. To assess spatial learning and memory, ASO(SNCA) or PBS-injected APP and non-transgenic (NTG) mice, and separate groups of SNCA-null mice, were tested on the Barnes circular maze. Hippocampal slice electrophysiology and transcriptomic profiling were used to explore synaptic function and differential gene expression between groups. Reduction of SNCA transcripts alleviated cognitive deficits in male transgenic animals, but surprisingly, not in females. To determine the functional cause of this differential effect, we assessed memory function in SNCA-null mice. Learning and memory were intact in male mice but impaired in female animals, revealing that the role of alpha Syn on cognitive function is sex-specific. Transcriptional analyses identified a differentially expressed gene network centered around EGR1, a central modulator of learning and memory, in the hippocampi of SNCA-null mice. Thus, these novel results demonstrate that the function of alpha Syn on memory differs between male and female brains.This work was supported by grants from the National Institutes of Health (NIH) to SEL (RF1-AG044342, RF1-AG070296, R21-AG065693, R01-AG077743, R01-NS092918, R01-AG062135 and R56-NS113549), to MKL (AG062135, NS108686, NS086074, NS092093). Training grant support for graduate students (T32-NS105604). This study was supported by a grant from the Winston and Maxine Wallin Neuroscience Discovery Fund. Additional support included start-up funds from the University of Minnesota Foundation and bridge funds from the Institute of Translational Neuroscience to SEL.BMC202320232022info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10810/59487reponame:Addi. Archivo Digital para la Docencia y la Investigacióninstname:Universidad del País VascoIngléshttps://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-022-01480-yinfo:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/3.0/es/© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the dataAtribución 3.0 Españaoai:addi.ehu.eus:10810/594872026-06-18T09:23:17Z
dc.title.none.fl_str_mv SNCA genetic lowering reveals differential cognitive function of alpha-synuclein dependent on sex
title SNCA genetic lowering reveals differential cognitive function of alpha-synuclein dependent on sex
spellingShingle SNCA genetic lowering reveals differential cognitive function of alpha-synuclein dependent on sex
Brown, Jennifer L.
alpha-synuclein
spatial memory
sex
antisense oligonucleotide
synucleinopathy
Alzheimer's disease
early growth response 1
title_short SNCA genetic lowering reveals differential cognitive function of alpha-synuclein dependent on sex
title_full SNCA genetic lowering reveals differential cognitive function of alpha-synuclein dependent on sex
title_fullStr SNCA genetic lowering reveals differential cognitive function of alpha-synuclein dependent on sex
title_full_unstemmed SNCA genetic lowering reveals differential cognitive function of alpha-synuclein dependent on sex
title_sort SNCA genetic lowering reveals differential cognitive function of alpha-synuclein dependent on sex
dc.creator.none.fl_str_mv Brown, Jennifer L.
Hart, Damyan W.
Boyle, Gabriel E.
Brown, Taylor G.
LaCroix, Michael
Baraibar Sierra, Andrés Mateo
Pelzel, Ross
Kim, Minwoo
Sherman, Mathew A.
Boes, Samuel
Sung, Michelle
Cole, Tracy
Lee, Michael K.
Araque, Alfonso
Lesne, Sylvain E.
author Brown, Jennifer L.
author_facet Brown, Jennifer L.
Hart, Damyan W.
Boyle, Gabriel E.
Brown, Taylor G.
LaCroix, Michael
Baraibar Sierra, Andrés Mateo
Pelzel, Ross
Kim, Minwoo
Sherman, Mathew A.
Boes, Samuel
Sung, Michelle
Cole, Tracy
Lee, Michael K.
Araque, Alfonso
Lesne, Sylvain E.
author_role author
author2 Hart, Damyan W.
Boyle, Gabriel E.
Brown, Taylor G.
LaCroix, Michael
Baraibar Sierra, Andrés Mateo
Pelzel, Ross
Kim, Minwoo
Sherman, Mathew A.
Boes, Samuel
Sung, Michelle
Cole, Tracy
Lee, Michael K.
Araque, Alfonso
Lesne, Sylvain E.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv alpha-synuclein
spatial memory
sex
antisense oligonucleotide
synucleinopathy
Alzheimer's disease
early growth response 1
topic alpha-synuclein
spatial memory
sex
antisense oligonucleotide
synucleinopathy
Alzheimer's disease
early growth response 1
description Antisense oligonucleotide (ASO) therapy for neurological disease has been successful in clinical settings and its potential has generated hope for Alzheimer's disease (AD). We previously described that ablating SNCA encoding for alpha-synuclein (alpha Syn) in a mouse model of AD was beneficial. Here, we sought to demonstrate whether transient reduction of alpha Syn expression using ASO(SNCA) could be therapeutic in a mouse model of AD. The efficacy of the ASO(SNCA) was measured via immunocytochemistry, RT-qPCR and western blotting. To assess spatial learning and memory, ASO(SNCA) or PBS-injected APP and non-transgenic (NTG) mice, and separate groups of SNCA-null mice, were tested on the Barnes circular maze. Hippocampal slice electrophysiology and transcriptomic profiling were used to explore synaptic function and differential gene expression between groups. Reduction of SNCA transcripts alleviated cognitive deficits in male transgenic animals, but surprisingly, not in females. To determine the functional cause of this differential effect, we assessed memory function in SNCA-null mice. Learning and memory were intact in male mice but impaired in female animals, revealing that the role of alpha Syn on cognitive function is sex-specific. Transcriptional analyses identified a differentially expressed gene network centered around EGR1, a central modulator of learning and memory, in the hippocampi of SNCA-null mice. Thus, these novel results demonstrate that the function of alpha Syn on memory differs between male and female brains.
publishDate 2022
dc.date.none.fl_str_mv 2022
2023
2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10810/59487
url http://hdl.handle.net/10810/59487
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-022-01480-y
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by/3.0/es/
Atribución 3.0 España
eu_rights_str_mv openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/3.0/es/
Atribución 3.0 España
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv BMC
publisher.none.fl_str_mv BMC
dc.source.none.fl_str_mv reponame:Addi. Archivo Digital para la Docencia y la Investigación
instname:Universidad del País Vasco
instname_str Universidad del País Vasco
reponame_str Addi. Archivo Digital para la Docencia y la Investigación
collection Addi. Archivo Digital para la Docencia y la Investigación
repository.name.fl_str_mv
repository.mail.fl_str_mv
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