title: CASPR2 forms a complex with GPR37 via MUPP1 but not with GPR37(R558Q), an autism spectrum disorder-related mutation.
abstract: Autism spectrum disorder (ASD) is a developmental brain disorder. Mutations in synaptic components including synaptic adhesion molecules have been found in ASD patients. Contactin-associated protein-like 2 (CASPR2) is one of the synaptic adhesion molecules associated with ASD. CASPR2 forms a complex with receptors via interaction with multiple PDZ domain protein 1 (MUPP1). Little is known about the relationship between impaired CASPR2-MUPP1-receptor complex and the pathogenesis of ASD. GPR37 is a receptor for survival factors. We recently identified mutations including R558Q in the G-protein-coupled receptor 37 (GPR37) gene in ASD patients. The mutated GPR37s accumulate in the endoplasmic reticulum. In this study, we show that GPR37 is a component of the CASPR2-MUPP1 receptor complex in the mouse brain. CASPR2 and GPR37 mainly interacted with the PDZ3 and PDZ11 domains of MUPP1, respectively. Compared to GPR37, GPR37(R558Q) slightly interacted with MUPP1 and caused dendritic alteration. GPR37, but not GPR37(R558Q) nor GPR37-deltaC which lacks its PDZ binding domain, was transported to the cell surface by MUPP1. In primary hippocampal neurons, GPR37 co-localized with MUPP1 and CASPR2 at the synapse, but not GPR37(R558Q). Thus, ASD-related mutation of GPR37 may cause the impaired CASPR2-MUPP1-GPR37 complex on the dendrites associated with one of the pathogenesis of ASD. In this study, we identified that GPR37 is a component of the MUPP1 and CASPR2 receptor complex. Autism deleterious mutated GPR37(R558Q) slightly interacts with MUPP1 and retains in ER, resulting in dendritic alteration. In neuron, GPR37, but not GPR37(R558Q), is transported to the dendrite and synapse by MUPP1. Thus, ASD-related mutation of GPR37 may cause the impaired CASPR2-MUPP1-GPR37 complex on the dendrites associated with one of the pathogenesis of ASD.
authors.affiliation: International University of Health and Welfare, Otawara, Tochigi, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tanabe
authors.affiliation: International University of Health and Welfare, Otawara, Tochigi, Japan.|Department of Pediatrics, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Fujita-Jimbo
authors.affiliation: International University of Health and Welfare, Otawara, Tochigi, Japan.
authors.forename: Mariko Y
authors.initials: MY
authors.lastname: Momoi
authors.affiliation: International University of Health and Welfare, Otawara, Tochigi, Japan.|Department of Pathophysiology, Tokyo Medical University, Shinjuku, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Momoi
mesh_terms: D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002659:Child Development Disorders, Pervasive / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*
chemical_list: C568163:CNTNAP2 protein, mouse; D002352:Carrier Proteins; C480827:GPR37 receptor, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C491749:Mpdz protein, rat; D009419:Nerve Tissue Proteins; D043562:Receptors, G-Protein-Coupled
keywords: CASPR2; GPR37; MUPP1; PDZ; autism spectrum disorder