Altered expression of Alzheimer's disease-related genes in the cerebellum of autistic patients: a model for disrupted brain connectome and therapy
Data(s) |
29/01/2016
29/01/2016
01/05/2014
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Resumo |
Autism and Alzheimer's disease (AD) are, respectively, neurodevelopmental and degenerative diseases with an increasing epidemiological burden. The AD-associated amyloid-beta precursor protein-alpha 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-values <0.05), 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 alpha-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 (Mg2+) 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. |
Identificador |
Cell Death and Disease 5 2014 : (2014) // Article ID e1250 2041-4889 http://hdl.handle.net/10810/17064 10.1038/cddis.2014.227 |
Idioma(s) |
eng |
Publicador |
Nature Publishing Group |
Relação |
http://www.nature.com/cddis/journal/v5/n5/full/cddis2014227a.html#abs |
Direitos |
Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution-NonCommercial- ShareAlike 3.0 Unported License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/ licenses/by-nc-sa/3.0/ info:eu-repo/semantics/openAccess |
Palavras-Chave | #proliferation #mitochondria #APP #magnesium #rapamycin #amiloyd-precursor-protein #regulated proteolysis #spectrum disorders #cognitive deficits #RNA interference #gamma-secretase #MNDA receptors #cell-survival #mouse model #SAPP-ALPHA |
Tipo |
info:eu-repo/semantics/article |