title: 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.
authors.affiliation: Division of Differentiation and Development, National Institute of Neuroscience, Kodaira, Tokyo, Japan.
authors.forename: E
authors.initials: E
authors.lastname: Fujita
authors.forename: H
authors.initials: H
authors.lastname: Dai
authors.forename: Y
authors.initials: Y
authors.lastname: Tanabe
authors.forename: Y
authors.initials: Y
authors.lastname: Zhiling
authors.forename: T
authors.initials: T
authors.lastname: Yamagata
authors.forename: T
authors.initials: T
authors.lastname: Miyakawa
authors.forename: M
authors.initials: M
authors.lastname: Tanokura
authors.forename: M Y
authors.initials: MY
authors.lastname: Momoi
authors.forename: T
authors.initials: T
authors.lastname: Momoi
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics* / Q000378:metabolism; D002675:Child, Preschool; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D007136:Immunoglobulins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051379:Mice; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010654:Phenylbutyrates / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D020123:Sirolimus / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000900:Anti-Bacterial Agents; C403514:CADM1 protein, human; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D015816:Cell Adhesion Molecules, Neuronal; C497250:Ddit3 protein, mouse; D007136:Immunoglobulins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010654:Phenylbutyrates; C098004:neuroligin 3; D051742:Transcription Factor CHOP; C075773:4-phenylbutyric acid; D020123:Sirolimus