Repositório Digital

A- A A+

Altered expression of Alzheimer’s disease-related genes in the cerebellum of autistic patients : a model for disrupted brain connectome and therapy

.

Altered expression of Alzheimer’s disease-related genes in the cerebellum of autistic patients : a model for disrupted brain connectome and therapy

Mostrar registro completo

Estatísticas

Título Altered expression of Alzheimer’s disease-related genes in the cerebellum of autistic patients : a model for disrupted brain connectome and therapy
Autor 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
Abstract 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.
Contido em Cell Death and Disease. [New York]. Vol. 5, no. 5 (May 2014), e1250 [13 p.]
Assunto Apoptose
Cerebelo
Doença de Alzheimer
Genes
Receptores de glutamato
Transtorno autístico
Origem Estrangeiro
Tipo Artigo de periódico
URI http://hdl.handle.net/10183/168914
Arquivos Descrição Formato
000937077.pdf (6.150Mb) Texto completo Adobe PDF Visualizar/abrir

Este item está licenciado na Creative Commons License

Este item aparece na(s) seguinte(s) coleção(ões)


Mostrar registro completo

Percorrer



  • O autor é titular dos direitos autorais dos documentos disponíveis neste repositório e é vedada, nos termos da lei, a comercialização de qualquer espécie sem sua autorização prévia.
    Projeto gráfico elaborado pelo Caixola - Clube de Criação Fabico/UFRGS Powered by DSpace software, Version 1.8.1.