Journal
BIOCHEMICAL JOURNAL
Volume 473, Issue -, Pages 423-434Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20150274
Keywords
autism; ER stress; molecular chaperones; neuroligin; protein misfolding; unfolded protein response
Categories
Funding
- Compagnia San Paolo
- Sapienza University of Rome
- Pasteur Institute - Cenci Bolognetti Foundation
- National Institutes of Health [MH092906]
- Robert Wood Johnson Foundation [67038]
- Governor's Council for Medical Research and Treatment of Autism [CAUT14APL028]
- [G1002610]
- MRC [G0601840, G1002610] Funding Source: UKRI
- Medical Research Council [G1002610, G0601840] Funding Source: researchfish
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available