Altered expression of Alzheimer’s disease-related genes in the cerebellum of autistic patients : a model for disrupted brain connectome and therapy
Autor(a) principal: | |
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Data de Publicação: | 2014 |
Outros Autores: | , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UFRGS |
Texto Completo: | http://hdl.handle.net/10183/168914 |
Resumo: | Autism and Alzheimer’s disease (AD) are, respectively, neurodevelopmental and degenerative diseases with an increasing epidemiological burden. The AD-associated amyloid-b precursor protein-a has been shown to be elevated in severe autism, leading to the ‘anabolic hypothesis’ of its etiology. Here we performed a focused microarray analysis of genes belonging to NOTCH and WNT signaling cascades, as well as genes related to AD and apoptosis pathways in cerebellar samples from autistic individuals, to provide further evidence for pathological relevance of these cascades for autism. By using the limma package from R and false discovery rate, we demonstrated that 31% (116 out of 374) of the genes belonging to these pathways displayed significant changes in expression (corrected P-valueso0.05), with mitochondria-related genes being the most downregulated. We also found upregulation of GRIN1, the channel-forming subunit of NMDA glutamate receptors, and MAP3K1, known activator of the JNK and ERK pathways with anti-apoptotic effect. Expression of PSEN2 (presinilin 2) and APBB1 (or F65) were significantly lower when compared with control samples. Based on these results, we propose a model of NMDA glutamate receptor-mediated ERK activation of a-secretase activity and mitochondrial adaptation to apoptosis that may explain the early brain overgrowth and disruption of synaptic plasticity and connectome in autism. Finally, systems pharmacology analyses of the model that integrates all these genes together (NOWADA) highlighted magnesium (Mg2þ) and rapamycin as most efficient drugs to target this network model in silico. Their potential therapeutic application, in the context of autism, is therefore discussed. |
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Zeidán-Chuliá, FaresOliveira, Ben Hur Neves deSalmina, Alla B.Casanova, Manuel F.Gelain, Daniel PensNoda, MamiVerkhratsky, AlexeiMoreira, Jose Claudio Fonseca2017-09-27T02:25:25Z20142041-4889http://hdl.handle.net/10183/168914000937077Autism and Alzheimer’s disease (AD) are, respectively, neurodevelopmental and degenerative diseases with an increasing epidemiological burden. The AD-associated amyloid-b precursor protein-a has been shown to be elevated in severe autism, leading to the ‘anabolic hypothesis’ of its etiology. Here we performed a focused microarray analysis of genes belonging to NOTCH and WNT signaling cascades, as well as genes related to AD and apoptosis pathways in cerebellar samples from autistic individuals, to provide further evidence for pathological relevance of these cascades for autism. By using the limma package from R and false discovery rate, we demonstrated that 31% (116 out of 374) of the genes belonging to these pathways displayed significant changes in expression (corrected P-valueso0.05), with mitochondria-related genes being the most downregulated. We also found upregulation of GRIN1, the channel-forming subunit of NMDA glutamate receptors, and MAP3K1, known activator of the JNK and ERK pathways with anti-apoptotic effect. Expression of PSEN2 (presinilin 2) and APBB1 (or F65) were significantly lower when compared with control samples. Based on these results, we propose a model of NMDA glutamate receptor-mediated ERK activation of a-secretase activity and mitochondrial adaptation to apoptosis that may explain the early brain overgrowth and disruption of synaptic plasticity and connectome in autism. Finally, systems pharmacology analyses of the model that integrates all these genes together (NOWADA) highlighted magnesium (Mg2þ) and rapamycin as most efficient drugs to target this network model in silico. Their potential therapeutic application, in the context of autism, is therefore discussed.application/pdfengCell Death and Disease. [New York]. Vol. 5, no. 5 (May 2014), e1250 [13 p.]Doença de AlzheimerGenesCerebeloTranstorno autísticoTranstorno do espectro autistaReceptores de glutamatoApoptoseAltered expression of Alzheimer’s disease-related genes in the cerebellum of autistic patients : a model for disrupted brain connectome and therapyEstrangeiroinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFRGSinstname:Universidade Federal do Rio Grande do Sul (UFRGS)instacron:UFRGSORIGINAL000937077.pdf000937077.pdfTexto completo (inglês)application/pdf6150495http://www.lume.ufrgs.br/bitstream/10183/168914/1/000937077.pdf1100b0bca5e1ed11829daffb6c67cec4MD51TEXT000937077.pdf.txt000937077.pdf.txtExtracted Texttext/plain67181http://www.lume.ufrgs.br/bitstream/10183/168914/2/000937077.pdf.txtdc15ef31e00d9e2abea242e6f61034cbMD52THUMBNAIL000937077.pdf.jpg000937077.pdf.jpgGenerated Thumbnailimage/jpeg2141http://www.lume.ufrgs.br/bitstream/10183/168914/3/000937077.pdf.jpgc7c4a2730e5563e0646ee506b32b4417MD5310183/1689142021-09-18 04:45:37.350191oai:www.lume.ufrgs.br:10183/168914Repositório de PublicaçõesPUBhttps://lume.ufrgs.br/oai/requestopendoar:2021-09-18T07:45:37Repositório Institucional da UFRGS - Universidade Federal do Rio Grande do Sul (UFRGS)false |
dc.title.pt_BR.fl_str_mv |
Altered expression of Alzheimer’s disease-related genes in the cerebellum of autistic patients : a model for disrupted brain connectome and therapy |
title |
Altered expression of Alzheimer’s disease-related genes in the cerebellum of autistic patients : a model for disrupted brain connectome and therapy |
spellingShingle |
Altered expression of Alzheimer’s disease-related genes in the cerebellum of autistic patients : a model for disrupted brain connectome and therapy Zeidán-Chuliá, Fares Doença de Alzheimer Genes Cerebelo Transtorno autístico Transtorno do espectro autista Receptores de glutamato Apoptose |
title_short |
Altered expression of Alzheimer’s disease-related genes in the cerebellum of autistic patients : a model for disrupted brain connectome and therapy |
title_full |
Altered expression of Alzheimer’s disease-related genes in the cerebellum of autistic patients : a model for disrupted brain connectome and therapy |
title_fullStr |
Altered expression of Alzheimer’s disease-related genes in the cerebellum of autistic patients : a model for disrupted brain connectome and therapy |
title_full_unstemmed |
Altered expression of Alzheimer’s disease-related genes in the cerebellum of autistic patients : a model for disrupted brain connectome and therapy |
title_sort |
Altered expression of Alzheimer’s disease-related genes in the cerebellum of autistic patients : a model for disrupted brain connectome and therapy |
author |
Zeidán-Chuliá, Fares |
author_facet |
Zeidán-Chuliá, Fares Oliveira, Ben Hur Neves de Salmina, Alla B. Casanova, Manuel F. Gelain, Daniel Pens Noda, Mami Verkhratsky, Alexei Moreira, Jose Claudio Fonseca |
author_role |
author |
author2 |
Oliveira, Ben Hur Neves de Salmina, Alla B. Casanova, Manuel F. Gelain, Daniel Pens Noda, Mami Verkhratsky, Alexei Moreira, Jose Claudio Fonseca |
author2_role |
author author author author author author author |
dc.contributor.author.fl_str_mv |
Zeidán-Chuliá, Fares Oliveira, Ben Hur Neves de Salmina, Alla B. Casanova, Manuel F. Gelain, Daniel Pens Noda, Mami Verkhratsky, Alexei Moreira, Jose Claudio Fonseca |
dc.subject.por.fl_str_mv |
Doença de Alzheimer Genes Cerebelo Transtorno autístico Transtorno do espectro autista Receptores de glutamato Apoptose |
topic |
Doença de Alzheimer Genes Cerebelo Transtorno autístico Transtorno do espectro autista Receptores de glutamato Apoptose |
description |
Autism and Alzheimer’s disease (AD) are, respectively, neurodevelopmental and degenerative diseases with an increasing epidemiological burden. The AD-associated amyloid-b precursor protein-a has been shown to be elevated in severe autism, leading to the ‘anabolic hypothesis’ of its etiology. Here we performed a focused microarray analysis of genes belonging to NOTCH and WNT signaling cascades, as well as genes related to AD and apoptosis pathways in cerebellar samples from autistic individuals, to provide further evidence for pathological relevance of these cascades for autism. By using the limma package from R and false discovery rate, we demonstrated that 31% (116 out of 374) of the genes belonging to these pathways displayed significant changes in expression (corrected P-valueso0.05), with mitochondria-related genes being the most downregulated. We also found upregulation of GRIN1, the channel-forming subunit of NMDA glutamate receptors, and MAP3K1, known activator of the JNK and ERK pathways with anti-apoptotic effect. Expression of PSEN2 (presinilin 2) and APBB1 (or F65) were significantly lower when compared with control samples. Based on these results, we propose a model of NMDA glutamate receptor-mediated ERK activation of a-secretase activity and mitochondrial adaptation to apoptosis that may explain the early brain overgrowth and disruption of synaptic plasticity and connectome in autism. Finally, systems pharmacology analyses of the model that integrates all these genes together (NOWADA) highlighted magnesium (Mg2þ) and rapamycin as most efficient drugs to target this network model in silico. Their potential therapeutic application, in the context of autism, is therefore discussed. |
publishDate |
2014 |
dc.date.issued.fl_str_mv |
2014 |
dc.date.accessioned.fl_str_mv |
2017-09-27T02:25:25Z |
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http://hdl.handle.net/10183/168914 |
dc.identifier.issn.pt_BR.fl_str_mv |
2041-4889 |
dc.identifier.nrb.pt_BR.fl_str_mv |
000937077 |
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http://hdl.handle.net/10183/168914 |
dc.language.iso.fl_str_mv |
eng |
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dc.relation.ispartof.pt_BR.fl_str_mv |
Cell Death and Disease. [New York]. Vol. 5, no. 5 (May 2014), e1250 [13 p.] |
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openAccess |
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