GM1 as Adjuvant of Innovative Therapies for Cystic Fibrosis Disease

International Journal of Molecular Sciences

Elena Chiricozzi¹  Sandro Sonnino¹  Rosaria Bassi¹  Giulia Mancini¹  Nicoletta Loberto¹  Laura Mauri¹  Massimo Aureli¹  Domitilla Schiumarini¹  Giuseppe Lippi²  Giulio Cabrini²  Debora Olioso²  MariaCristina Dechecchi²  Anna Tamanini³  Nicoletta Pedemonte⁴  Emanuela Pesce⁴ 

[1] Department of Medical Biotechnology and Translational Medicine, University of Milano, LITA, Via Fratelli Cervi 93, 20090 Segrate, Milano, Italy;Section of Clinical Biochemistry, Department of Neurosciences, Biomedicine and Movement, University of Verona, 37134 Verona, Italy;Section of Molecular Pathology, Department of Pathology and Diagnostics, University Hospital of Verona, 37126 Verona, Italy;U.O.C. Genetica Medica, IRCCS Giannina Gaslini, 16147 Genova, Italy;

关键词: ganglioside GM1;    membrane domain;    cystic fibrosis;    CFTR;    correctors;    potentiators;   

DOI  :  10.3390/ijms21124486

来源: DOAJ

【 摘 要 】

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein is expressed at the apical plasma membrane (PM) of different epithelial cells. The most common mutation responsible for the onset of cystic fibrosis (CF), F508del, inhibits the biosynthesis and transport of the protein at PM, and also presents gating and stability defects of the membrane anion channel upon its rescue by the use of correctors and potentiators. This prompted a multiple drug strategy for F508delCFTR aimed simultaneously at its rescue, functional potentiation and PM stabilization. Since ganglioside GM1 is involved in the functional stabilization of transmembrane proteins, we investigated its role as an adjuvant to increase the effectiveness of CFTR modulators. According to our results, we found that GM1 resides in the same PM microenvironment as CFTR. In CF cells, the expression of the mutated channel is accompanied by a decrease in the PM GM1 content. Interestingly, by the exogenous administration of GM1, it becomes a component of the PM, reducing the destabilizing effect of the potentiator VX-770 on rescued CFTR protein expression/function and improving its stabilization. This evidence could represent a starting point for developing innovative therapeutic strategies based on the co-administration of GM1, correctors and potentiators, with the aim of improving F508del CFTR function.

【 授权许可】

Unknown