5'-adenosine monophosphate mediated cooling treatment enhances ΔF508-Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) stability in vivo.

Yueqiang Zhang,Cheng Chi Lee,Zhaoyang Zhao,William G O’Brien

doi:10.1186/s12929-015-0178-3

Abstract

BackgroundGene mutations that produce misprocessed proteins are linked to many human disorders. Interestingly, some misprocessed proteins retained their biological function when stabilized by low temperature treatment of cultured cells in vitro. Here we investigate whether low temperature treatment in vivo can rescue misfolded proteins by applying 5’-AMP mediated whole body cooling to a Cystic Fibrosis (CF) mouse model carrying a mutant cystic fibrosis transmembrane conductance regulator (CFTR) with a deletion of the phenylalanine residue in position 508 (ΔF508-CFTR). Low temperature treatment of cultured cells was previously shown to be able to alleviate the processing defect of ΔF508-CFTR, enhancing its plasma membrane localization and its function in mediating chloride ion transport.ResultsHere, we report that whole body cooling enhanced the retention of ΔF508-CFTR in intestinal epithelial cells. Functional analysis based on β-adrenergic dependent salivary secretion and post-natal mortality rate revealed a moderate but significant improvement in treated compared with untreated CF mice.ConclusionsOur findings demonstrate that temperature sensitive processing of mutant proteins can be responsive to low temperature treatment in vivo.

Highlights

Gene mutations that produce misprocessed proteins are linked to many human disorders
To assess the stability of ΔF508-Cystic fibrosis transmembrane conductance regulator (CFTR) protein after whole body cooling, we examined duodenal tissues from Cystic Fibrosis (CF) mice collected at 24 h, 48 h and six days post-treatment, using corresponding tissues from wild type mice as controls (Fig. 1a)
5’-Adenosine monophosphate (5’-AMP) induced whole body cooling treatments improve CF mouse survival we examined whether CF mice that were given multiple treatments with the AMP induced hypometabolism (AIHM) whole body cooling regime had reduced mortality

Summary

Introduction

Gene mutations that produce misprocessed proteins are linked to many human disorders. In a healthy cellular environment, misfolded proteins fail to pass the “quality control” of the endoplasmic reticulum (ER) and are retained and selectively degraded without being exported. These are typically described as trafficking defects since the misfolded proteins fail to reach their target sites. These disorders result from the loss of functional protein, as in CF [3,4,5].

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