Neuroligin 3 (NLGN3) and neurexins (NRXNs) constitute a canonical transsynaptic cell-adhesion pair, which has been implicated in autism. In autism spectrum disorder (ASD) development of sociality can be impaired. However, the molecular mechanism underlying NLGN3-mediated social development is unclear. Here, we identify non-canonical interactions between NLGN3 and protein tyrosine phosphatase δ (PTPδ) splice variants, competing with NRXN binding. NLGN3-PTPδ complex structure revealed a splicing-dependent interaction mode and competition mechanism between PTPδ and NRXNs. Mice carrying a NLGN3 mutation that selectively impairs NLGN3-NRXN interaction show increased sociability, whereas mice where the NLGN3-PTPδ interaction is impaired exhibit impaired social behavior and enhanced motor learning, with imbalance in excitatory/inhibitory synaptic protein expressions, as reported in the Nlgn3 R451C autism model. At neuronal level, the autism-related Nlgn3 R451C mutation causes selective impairment in the non-canonical pathway. Our findings suggest that canonical and non-canonical NLGN3 pathways compete and regulate the development of sociality.
Autism Spectrum Disorder/genetics , Calcium-Binding Proteins/metabolism , Cell Adhesion Molecules, Neuronal/metabolism , Membrane Proteins/metabolism , Nerve Tissue Proteins/metabolism , Neural Cell Adhesion Molecules/metabolism , Neurons/metabolism , Receptor-Like Protein Tyrosine Phosphatases, Class 2/metabolism , Amino Acid Sequence , Animals , Autism Spectrum Disorder/metabolism , Behavior Rating Scale , Calcium-Binding Proteins/chemistry , Calcium-Binding Proteins/genetics , Cell Adhesion Molecules, Neuronal/chemistry , Cell Adhesion Molecules, Neuronal/genetics , Disease Models, Animal , Female , HEK293 Cells , Humans , Male , Membrane Proteins/chemistry , Membrane Proteins/genetics , Mice , Mice, Knockout , Mice, Transgenic , Mutation , Nerve Tissue Proteins/chemistry , Nerve Tissue Proteins/genetics , Neural Cell Adhesion Molecules/chemistry , Neural Cell Adhesion Molecules/genetics , Protein Domains , Protein Splicing , Receptor-Like Protein Tyrosine Phosphatases, Class 2/chemistry , Receptor-Like Protein Tyrosine Phosphatases, Class 2/genetics , Recombinant Proteins , Signal Transduction/genetics , Signal Transduction/physiology , Social Behavior , Synapses/genetics
Autism Spectrum Disorders (ASD) are a group of neurodevelopmental disorders and are well recognized to be biologically heterogeneous in which various factors are associated, including genetic, metabolic, and environmental ones. Despite its high prevalence, only a few drugs have been approved for the treatment of ASD. Therefore, extensive studies have been conducted to identify ASD risk genes and novel drug targets. Since many genes and many other factors are associated with ASD, various bioinformatics methods have also been developed for the analysis of ASD. In this paper, we review bioinformatics methods for analyzing ASD data with the focus on computational aspects. We classify existing methods into two categories: (i) methods based on genomic variants and gene expression data, and (ii) methods using biological networks, which include gene co-expression networks and protein-protein interaction networks. Next, for each method, we provide an overall flow and elaborate on the computational techniques used. We also briefly review other approaches and discuss possible future directions and strategies for developing bioinformatics approaches to analyze ASD.
Autism Spectrum Disorder , Computational Biology , Autism Spectrum Disorder/drug therapy , Autism Spectrum Disorder/genetics , Genomics , Humans
OBJECTIVE: The aim of this study was to confirm the effects of chronic kidney disease (CKD) and anemia on physical function and to clarify whether the interaction between CKD and anemia has an additive effect. DESIGN: Eligible subjects were chronic heart failure (HF) patients who were discharged between March 2007 and August 2009. A total of 102 chronic HF patients (33% females; mean age: 68 ± 14 years) were enrolled in the present study. CKD was defined as an estimated glomerular filtration rate of <60 ml/min/1.73 m(2), and anemia was defined as a hemoglobin level of <12 g/dl in males and of <11 g/dl in females. The Short Physical Performance Battery (SPPB) was used to assess physical function. RESULTS: The adjusted mean SPPB score was lower in patients with both CKD and anemia than in those with neither of the diseases or with either disease alone (p < 0.05). CONCLUSION: This study found that CKD and anemia are independently associated with reduced physical function.
