Autism-associated R451C mutation in neuroligin3 leads to activation of the unfolded protein response in a PC12 Tet-On inducible system

Ulbrich, Lisa; Favaloro, Flores Lietta; Trobiani, Laura; Marchetti, Valentina; Patel, Vruti; Pascucci, Tiziana; Comoletti, Davide; Marciniak, Stefan J.; Jaco, Antonella De

doi:10.1042/bj20150274

Cited by 31 publications

(41 citation statements)

References 47 publications

(59 reference statements)

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“…The current knowledge regarding the role of ER stress in the pathophysiology of ASD is mainly based on data from autism-associated mutations in synaptic genes such as NLGN3, CNTNAP2, and CADM1 [19,20,21,22,23,24]. Our data provide the first evidence of altered ER stress genes in the brain of ASD subjects.…”

Section: Resultsmentioning

confidence: 59%

“…In particular, genetic variations in several synaptic genes implicated in ASD have been shown to induce ER stress genes. Overexpression of neuroligin (NLGN) 3 mutant has been shown to activate the UPR downstream of the stress sensors ATF6, IRE1, and PERK [21]. Mutated GPR85 resulted in ER stress and impaired dendrite formation of hippocampal neurons [22].…”

Section: Introductionmentioning

confidence: 99%

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Altered Expression of Endoplasmic Reticulum Stress-Related Genes in the Middle Frontal Cortex of Subjects with Autism Spectrum Disorder

2017

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The endoplasmic reticulum (ER) is an important organelle responsible for the folding and sorting of proteins. Disturbances in ER homeostasis can trigger a cellular response known as the unfolded protein response, leading to accumulation of unfolded or misfolded proteins in the ER lumen called ER stress. A number of recent studies suggest that mutations in autism spectrum disorder (ASD)-susceptible synaptic genes induce ER stress. However, it is not known whether ER stress-related genes are altered in the brain of ASD subjects. In the present study, we investigated the mRNA expression of ER stress-related genes (ATF4, ATF6, PERK, XBP1, sXBP1, CHOP, and IRE1) in the postmortem middle frontal gyrus of ASD and control subjects. RT-PCR analysis showed significant increases in the mRNA levels of ATF4, ATF6, PERK, XBP1, CHOP, and IRE1 in the middle frontal gyrus of ASD subjects. In addition, we found a significant positive association of mRNA levels of ER stress genes with the diagnostic score for stereotyped behavior in ASD subjects. These results, for the first time, provide the evidence of the dysregulation of ER stress genes in the brain of subjects with ASD.

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Section: Resultsmentioning

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Altered Expression of Endoplasmic Reticulum Stress-Related Genes in the Middle Frontal Cortex of Subjects with Autism Spectrum Disorder

2017

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“…The emerging evidence shows that ER stress is associated with the pathogenesis of autism(Fujita-Jimbo et al , 2015; Fujita et al , 2010; Momoi et al , 2010; Ulbrich et al , 2015). Genetic testing in individuals with autism has identified mutations in several genes encoding synaptic cell adhesion molecules, such as neuroligin-3 and -4 (NLGN-3 and -4)(Jamain et al , 2003) and cell adhesion molecule-1 (CADM-1)(Zhiling et al , 2008).…”

Section: Discussionmentioning

confidence: 99%

“…Genetic testing in individuals with autism has identified mutations in several genes encoding synaptic cell adhesion molecules, such as neuroligin-3 and -4 (NLGN-3 and -4)(Jamain et al , 2003) and cell adhesion molecule-1 (CADM-1)(Zhiling et al , 2008). It has been shown that mutated NLGN-3 and CADM-1 induce local misfolding and cause partial retention of proteins in the ER that lead to ER stress in PC12 and C2C5 cell models(Fujita, et al , 2010; Ulbrich, et al , 2015). Overexpression of mutated NLGN-3 leads to the activation of three ER stress signals, as well as their downstream genes, such as BiP and CHOP in PC12 cells(Ulbrich, et al , 2015).…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that mutated NLGN-3 and CADM-1 induce local misfolding and cause partial retention of proteins in the ER that lead to ER stress in PC12 and C2C5 cell models(Fujita, et al , 2010; Ulbrich, et al , 2015). Overexpression of mutated NLGN-3 leads to the activation of three ER stress signals, as well as their downstream genes, such as BiP and CHOP in PC12 cells(Ulbrich, et al , 2015). In addition to mutations in genes encoding synaptic adhesion molecules, mutations in the GPR85 gene that is located in the AD linkage locus 9 (AUTS9) on chromosome 7q31 are associated with autism(Fujita-Jimbo, et al , 2015).…”

Section: Discussionmentioning

confidence: 99%

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Cellular stress and apoptosis contribute to the pathogenesis of autism spectrum disorder

et al. 2018

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Autism results in significant morbidity and mortality in children. The functional and molecular changes in the autistic brains are unclear. The present study utilized autistic brain tissues from the National Institute of Child Health and Human Development's Brain Tissue Bank for the analysis of cellular and molecular changes in autistic brains. Three key brain regions, the hippocampus, the cerebellum, and the frontal cortex, in six cases of autistic brains and six cases of non-autistic brains from 6 to 16 years old deceased children, were analyzed. The current study investigated the possible roles of endoplasmic reticulum (ER) stress, oxidative stress, and apoptosis as molecular mechanisms underlying autism. The activation of three signals of ER stress (protein kinase R-like endoplasmic reticulum kinase, activating transcription factor 6, inositol-requiring enzyme 1 alpha) varies in different regions. The occurrence of ER stress leads to apoptosis in autistic brains. ER stress may result from oxidative stress because of elevated levels of the oxidative stress markers: 4-Hydroxynonenal and nitrotyrosine-modified proteins in autistic brains. These findings suggest that cellular stress and apoptosis may contribute to the autistic phenotype. Pharmaceuticals and/or dietary supplements, which can alleviate ER stress, oxidative stress and apoptosis, may be effective in ameliorating adverse phenotypes associated with autism.

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A Lipophilic 4‐Phenylbutyric Acid Derivative That Prevents Aggregation and Retention of Misfolded Proteins

Azoulay-Ginsburg

Trobiani

Setini

et al. 2020

Chemistry A European J

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Chemical chaperonesp reventprotein aggregation. However,t he use of chemicalc haperones as drugs against diseases due to protein aggregation is limitedb yt he very high active concentrations (mm range) required to mediate their effect. One of the most commonc hemical chaperones is 4-phenylbutyric acid (4-PBA). Despite itsu nfavorablep harmacokinetic properties, 4-PBA was approved as ad rug to treat ornithine cycled iseases.H ere, we report that 2-isopropyl-4-phenylbutanoic acid (5)h as been found to be 2-10fold more effective than 4-PBA in several in vitro modelso f protein aggregation.I mportantly,c ompound 5 reduced the secretion rate of autism-linked Arg451Cys Neuroligin3 (R451CN LGN3).[a] S. Azoulay-Ginsburg,L .L evy,P rof. A. Gruzman

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Autism-associated R451C mutation in neuroligin3 leads to activation of the unfolded protein response in a PC12 Tet-On inducible system

Abstract: The expression of the autism-related mutant R451C neuroligin3 activates the three branches of the unfolded protein response in neuronal-like PC12 cells and leads to up-regulation of the response target genes BiP and CHOP.

Cited by 31 publications

References 47 publications

Altered Expression of Endoplasmic Reticulum Stress-Related Genes in the Middle Frontal Cortex of Subjects with Autism Spectrum Disorder

Altered Expression of Endoplasmic Reticulum Stress-Related Genes in the Middle Frontal Cortex of Subjects with Autism Spectrum Disorder

Cellular stress and apoptosis contribute to the pathogenesis of autism spectrum disorder

A Lipophilic 4‐Phenylbutyric Acid Derivative That Prevents Aggregation and Retention of Misfolded Proteins

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