Autism associated R451C mutation in Neuroligin3 leads to the activation of the unfolded protein response in a PC12 Tet-On inducible system
Favaloro, Flores Lietta
de, Jaco Antonella
Neurolign 3 misfolding mutations and activation of the unfolded protein response
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Ulbrich, L., Favaloro, F. L., Trobiani, L., Marchetti, V., Patel, V., Pascucci, T., Comoletti, D., et al. (2015). Autism associated R451C mutation in Neuroligin3 leads to the activation of the unfolded protein response in a PC12 Tet-On inducible system. Biochemical Journal, 473 423-434. https://doi.org/10.1042/BJ20150274
Several forms of monogenic heritable autism spectrum disorders are associated to mutations in the neuroligin genes. The autism-linked substitution arginine 451 to cysteine (R451C) in neuroligin3induces local misfolding of its extracellular domain, causing partial retention in the endoplasmic reticulum (ER) of expressing cells. We have generated a PC12 Tet-On cell model system with inducible expression of wild type or R451C neuroligin3 to investigate if there is activation of the unfolded protein response (UPR) as a result of misfolded protein retention. As a positive control for protein misfolding, we also expressed the severely disrupted 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 signaling branches of the UPR downstream of the stress sensors ATF6, IRE1 and PERK. Each branch displayed different activation profiles that partially correlated with the degree of misfolding caused by each mutation. We also show that upregulation of BiP and CHOP was induced by both mutant proteins but not by wild type neuroligin3, both in proliferative cells and cells differentiated to a neuronal–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.
neuroligin, ER stress, unfolded protein response, autism, protein misfolding, molecular chaperones
This work was supported by: Compagnia San Paolo, Sapienza University of Rome and Pasteur Institute - Cenci Bolognetti Foundation grants to ADJ. SJM is a MRC Senior Clinical Research Fellow [MRC Ref G1002610]. This work was also supported by National Institutes of Health grants (MH092906), from the Robert Wood Johnson Foundation to the Child Health Institute of New Jersey [grant #67038] and to the Governor's Council for Medical Research and Treatment of Autism [CAUT14APL028] to D.C.
Alpha One Foundation (unknown)
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External DOI: https://doi.org/10.1042/BJ20150274
This record's URL: https://www.repository.cam.ac.uk/handle/1810/253181