Altered expression of Alzheimer's disease-related genes in the cerebellum of autistic patients: a model for disrupted brain connectome and therapy.
Autism and Alzheimer's disease (AD) are, respectively, neurodevelopmental and degenerative diseases with an increasing epidemiological burden. The AD-associated amyloid-β precursor protein-α 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 α-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 (Mg(2+)) 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.
Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
F
F
Zeidán-Chuliá
Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
B-H N
BH
de Oliveira
Department of Biochemistry, Medical, Pharmaceutical and Toxicological Chemistry, Krasnoyarsk State Medical University, Krasnoyarsk, Russia.
A B
AB
Salmina
Department of Psychiatry and Behavioral Sciences, University of Louisville, Louisville, KY, USA.
M F
MF
Casanova
Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
D P
DP
Gelain
Laboratory of Pathophysiology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
M
M
Noda
1] Faculty of Life Sciences, The University of Manchester, Manchester, UK [2] IKERBASQUE, Basque Foundation for Science, Bilbao, Spain [3] Department of Neurosciences, University of the Basque Country UPV/EHU, Leioa, Spain.
A
A
Verkhratsky
Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
J C F
JC
Moreira
D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D017209:Apoptosis / Q000235:genetics; D001321:Autistic Disorder / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D003198:Computer Simulation; D063132:Connectome; D030541:Databases, Genetic; D015195:Drug Design; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D006801:Humans; D058990:Molecular Targeted Therapy; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011379:Prognosis; D015398:Signal Transduction / Q000235:genetics; D049490:Systems Biology; D014158:Transcription, Genetic