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Autism spectrum disorder is related to endoplasmic reticulum stress induced by mutations in the synaptic cell adhesion molecule, CADM1.

ABSTRACT: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with an unknown molecular pathogenesis. A recent molecular focus has been the mutated neuroligin 3, neuroligin 3(R451C), in gain-of-function studies and for its role in induced impairment of synaptic function, but endoplasmic reticulum (ER) stress induced by mutated molecules also deserves investigation. We previously found two missense mutations, H246N and Y251S, in the gene-encoding synaptic cell adhesion molecule-1 (CADM1) in ASD patients, including cleavage of the mutated CADM1 and its intracellular accumulation. In this study, we found that the mutated CADM1 showed slightly reduced homophilic interactions in vitro but that most of its interactions persist. The mutated CADM1 also showed morphological abnormalities, including shorter dendrites, and impaired synaptogenesis in neurons. Wild-type CADM1 was partly localized to the ER of C2C5 cells, whereas mutated CADM1 mainly accumulated in the ER despite different sensitivities toward 4-phenyl butyric acid with chemical chaperone activity and rapamycin with promotion activity for degradation of the aggregated protein. Modeling analysis suggested a direct relationship between the mutations and the conformation alteration. Both mutated CADM1 and neuroligin 3(R451C) induced upregulation of C/EBP-homologous protein (CHOP), an ER stress marker, suggesting that in addition to the trafficking impairment, this CHOP upregulation may also be involved in ASD pathogenesis.

SUBMITTER: Fujita E

PROVIDER: S-EPMC3032316 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Autism spectrum disorder is related to endoplasmic reticulum stress induced by mutations in the synaptic cell adhesion molecule, CADM1.

Fujita E E Dai H H Tanabe Y Y Zhiling Y Y Yamagata T T Miyakawa T T Tanokura M M Momoi M Y MY Momoi T T

Cell death & disease 20100603

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with an unknown molecular pathogenesis. A recent molecular focus has been the mutated neuroligin 3, neuroligin 3(R451C), in gain-of-function studies and for its role in induced impairment of synaptic function, but endoplasmic reticulum (ER) stress induced by mutated molecules also deserves investigation. We previously found two missense mutations, H246N and Y251S, in the gene-encoding synaptic cell adhesion molecule-1 (CADM1) in ASD ...[more]

PMID: 21364653

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Project description:Endoplasmic reticulum (ER) stress has been demonstrated to play important roles in a variety of human diseases. However, their relevance to autism spectrum disorder (ASD) remains largely unknown. Herein, we aimed to investigate the expression patterns and potential roles of the ER stress regulators in ASD. The ASD expression profiles GSE111176 and GSE77103 were compiled from the Gene Expression Omnibus (GEO) database. ER stress score determined by the single sample gene set enrichment analysis (ssGSEA) was significantly higher in ASD patients. Differential analysis revealed that there were 37 ER stress regulators dysregulated in ASD. Based on their expression profile, the random forest and artificial neuron network techniques were applied to build a classifier that can effectively distinguish ASD from control samples among independent datasets. Weighted gene co-expression network analysis (WGCNA) screened out the turquoise module with 774 genes was closely related to the ER stress score. Through the overlapping results of the turquoise module and differential expression ER stress genes, hub regulators were gathered. The TF/miRNA-hub gene interaction networks were created. Furthermore, the consensus clustering algorithm was performed to cluster the ASD patients, and there were two ASD subclusters. Each subcluster has unique expression profiles, biological functions, and immunological characteristics. In ASD subcluster 1, the FAS pathway was more enriched, while subcluster 2 had a higher level of plasma cell infiltration as well as the BCR signaling pathway and interleukin receptor reaction reactivity. Finally, the Connectivity map (CMap) database was used to find prospective compounds that target various ASD subclusters. A total of 136 compounds were significantly enriched. In addition to some specific drugs which can effectively reverse the differential gene expression of each subcluster, we found that the PKC inhibitor BRD-K09991945 that targets Glycogen synthase kinase 3β (GSK3B) might have a therapeutic effect on both ASD subtypes that worth of the experimental validation. Our finding proved that ER stress plays a crucial role in the diversity and complexity of ASD, which may inform both mechanistic and therapeutic assessments of the disorder.

Dataset Information

Autism spectrum disorder is related to endoplasmic reticulum stress induced by mutations in the synaptic cell adhesion molecule, CADM1.

Publications

Autism spectrum disorder is related to endoplasmic reticulum stress induced by mutations in the synaptic cell adhesion molecule, CADM1.

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