ArticleThe Biochemical journal2016
Autism-associated R451C mutation in neuroligin3 leads to activation of the unfolded protein response in a PC12 Tet-On inducible system.
Article in The Biochemical journal, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 32 citations in OpenAlex.
- The potential ameliorative effect of mesenchymal stem cells-derived exosomes on cerebellar histopathology and their modifying role on PI3k-mTOR signaling in rat model of autism spectrum disorder.Journal of molecular histology · 2025Article
- Analyses of the autism-associated neuroligin-3 R451C mutation in human neurons reveal a gain-of-function synaptic mechanism.Molecular psychiatry · 2024Article
- Understanding the Unfolded Protein Response (UPR) Pathway: Insights into Neuropsychiatric Disorders and Therapeutic Potentials.Biomolecules & therapeutics · 2024Review
- Integrated analysis of endoplasmic reticulum stress regulators' expression identifies distinct subtypes of autism spectrum disorder.Frontiers in psychiatry · 2023Article
- Sleep deficiency as a driver of cellular stress and damage in neurological disorders.Sleep medicine reviews · 2022Review
- A Perspective on the Potential Involvement of Impaired Proteostasis in Neuropsychiatric Disorders.Biological psychiatry · 2022Review
- Assistance for Folding of Disease-Causing Plasma Membrane Proteins.Biomolecules · 2020Review
- The Unfolded Protein Response and Autophagy as Drug Targets in Neuropsychiatric Disorders.Frontiers in cellular neuroscience · 2020Review
- Proteomics Study of Peripheral Blood Mononuclear Cells (PBMCs) in Autistic Children.Frontiers in cellular neuroscience · 2019Article
- Cellular stress and apoptosis contribute to the pathogenesis of autism spectrum disorder.Autism research : official journal of the International Society for Autism Research · 2018Article
- Implication of Endoplasmic Reticulum Stress in Autism Spectrum Disorder.Neurochemical research · 2018Review
- Altered Expression of Endoplasmic Reticulum Stress-Related Genes in the Middle Frontal Cortex of Subjects with Autism Spectrum Disorder.Molecular neuropsychiatry · 2017Article
- ER stress and the unfolded protein response in neurodegeneration.Nature reviews. Neurology · 2017Review
- Proteolytic cleavage is required for functional neuroligin 2 maturation and trafficking in Drosophila.Journal of molecular cell biology · 2017Article
- Unbalance between Excitation and Inhibition in Phenylketonuria, a Genetic Metabolic Disease Associated with Autism.International journal of molecular sciences · 2017Article
- Transcriptional response ofRoyal Society open science · 2017Article
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Authors and funding
9 authors at 4 institutions in 1 country.
Funding
Abstract
Several forms of monogenic heritable autism spectrum disorders are associated with mutations in the neuroligin genes. The autism-linked substitution R451C in neuroligin3 induces local misfolding of its extracellular domain, causing partial retention in the ER (endoplasmic reticulum) of expressing cells. We have generated a PC12 Tet-On cell model system with inducible expression of wild-type or R451C neuroligin3 to investigate whether there is activation of the UPR (unfolded protein response) as a result of misfolded protein retention. As a positive control for protein misfolding, we also expressed the mutant G221R neuroligin3, which is known to be completely retained within the ER. Our data show that overexpression of either R451C or G221R mutant proteins leads to the activation of all three signalling branches of the UPR downstream of the stress sensors ATF6 (activating transcription factor 6), IRE1 (inositol-requiring enzyme 1) and PERK [PKR (dsRNA-dependent protein kinase)-like endoplasmic reticulum kinase]. Each branch displayed different activation profiles that partially correlated with the degree of misfolding caused by each mutation. We also show that up-regulation of BiP (immunoglobulin heavy-chain-binding protein) and CHOP [C/EBP (CCAAT/enhancer-binding protein)-homologous protein] was induced by both mutant proteins but not by wild-type neuroligin3, both in proliferative cells and cells differentiated to a neuron-like phenotype. Collectively, our data show that mutant R451C neuroligin3 activates the UPR in a novel cell model system, suggesting that this cellular response may have a role in monogenic forms of autism characterized by misfolding mutations.
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