Autism spectrum disorders are developmental syndromes (ASDs) characterized, at the neuronal level, by alterations in neurotransmission. Among the risk genes associated with ASD, mutations have been found in synaptic molecules such as the Neuroligins that are post-synaptic adhesion proteins. In particular, the R451C substitution in Neuroligin3 (NLGN3) was found in a Swedish family affected by ASD. It was shown by in vitro and in vivo studies, that this mutation affects the folding of the extracellular domain of NLGN3, causing a reduced exposure of the protein on the cell surface with its retention in the Endoplasmic Reticulum (ER) and the consequent activation of the unfolded protein response (UPR). We selected, from a library of 2662 drugs approved by the FDA, few compounds belonging to the family of Glucocorticoids (GCs) such as Aclometasone Dipropionate (AD), Denoside (D), Prednisolone Sodium Phosphate (PSP) and Dexamethasone (DEX) for improving the impaired trafficking of NLGN3 R451C protein. Our data show that GCs increase selectively protein levels of mutant NLGN3 by activating the glucocorticoid receptor (GR) in a dose and time-dependent manner. In particular, DEX promotes protein stability and its exposure on the cell surface. Our data also shows that, by reducing the ER-retention of the mutant protein, GCs mitigate ER stress, by lowering the activation of the three branches of UPR. Moreover, PDI levels were decreased by the GCs treatment, but levels of BiP and Grp94 were unchanged.
Effects of Glucocorticoid treatment on the impaired trafficking of R451C Neuroligin3 / Diamanti, Tamara; Trobiani, Laura; Bianchi, Sara; Guglielmo, Stefano; Perfetto, Camilla; Serafini, Federica; Setini, Andrea; DE JACO, Antonella. - (2021). (Intervento presentato al convegno 19th National Congress of the Italian Society for Neuroscience tenutosi a Brescia).
Effects of Glucocorticoid treatment on the impaired trafficking of R451C Neuroligin3
Tamara DiamantiPrimo
;Laura TrobianiSecondo
;Sara Bianchi;Andrea Setini;Antonella De Jaco.Ultimo
2021
Abstract
Autism spectrum disorders are developmental syndromes (ASDs) characterized, at the neuronal level, by alterations in neurotransmission. Among the risk genes associated with ASD, mutations have been found in synaptic molecules such as the Neuroligins that are post-synaptic adhesion proteins. In particular, the R451C substitution in Neuroligin3 (NLGN3) was found in a Swedish family affected by ASD. It was shown by in vitro and in vivo studies, that this mutation affects the folding of the extracellular domain of NLGN3, causing a reduced exposure of the protein on the cell surface with its retention in the Endoplasmic Reticulum (ER) and the consequent activation of the unfolded protein response (UPR). We selected, from a library of 2662 drugs approved by the FDA, few compounds belonging to the family of Glucocorticoids (GCs) such as Aclometasone Dipropionate (AD), Denoside (D), Prednisolone Sodium Phosphate (PSP) and Dexamethasone (DEX) for improving the impaired trafficking of NLGN3 R451C protein. Our data show that GCs increase selectively protein levels of mutant NLGN3 by activating the glucocorticoid receptor (GR) in a dose and time-dependent manner. In particular, DEX promotes protein stability and its exposure on the cell surface. Our data also shows that, by reducing the ER-retention of the mutant protein, GCs mitigate ER stress, by lowering the activation of the three branches of UPR. Moreover, PDI levels were decreased by the GCs treatment, but levels of BiP and Grp94 were unchanged.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.