Mostrar registro simples

dc.contributor.authorZeidán-Chuliá, Farespt_BR
dc.contributor.authorOliveira, Ben Hur Neves dept_BR
dc.contributor.authorSalmina, Alla B.pt_BR
dc.contributor.authorCasanova, Manuel F.pt_BR
dc.contributor.authorGelain, Daniel Penspt_BR
dc.contributor.authorNoda, Mamipt_BR
dc.contributor.authorVerkhratsky, Alexeipt_BR
dc.contributor.authorMoreira, Jose Claudio Fonsecapt_BR
dc.date.accessioned2017-09-27T02:25:25Zpt_BR
dc.date.issued2014pt_BR
dc.identifier.issn2041-4889pt_BR
dc.identifier.urihttp://hdl.handle.net/10183/168914pt_BR
dc.description.abstractAutism 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.en
dc.format.mimetypeapplication/pdfpt_BR
dc.language.isoengpt_BR
dc.relation.ispartofCell Death and Disease. [New York]. Vol. 5, no. 5 (May 2014), e1250 [13 p.]pt_BR
dc.rightsOpen Accessen
dc.subjectDoença de Alzheimerpt_BR
dc.subjectGenespt_BR
dc.subjectCerebelopt_BR
dc.subjectTranstorno autísticopt_BR
dc.subjectTranstorno do espectro autistapt_BR
dc.subjectReceptores de glutamatopt_BR
dc.subjectApoptosept_BR
dc.titleAltered expression of Alzheimer’s disease-related genes in the cerebellum of autistic patients : a model for disrupted brain connectome and therapypt_BR
dc.typeArtigo de periódicopt_BR
dc.identifier.nrb000937077pt_BR
dc.type.originEstrangeiropt_BR


Thumbnail
   

Este item está licenciado na Creative Commons License

Mostrar registro simples