Analysis of the asthma susceptibility gene ORMDL3 using the model organism Drosophila melanogaster

Asthma bronchiale is a chronic inflammatory disease of the lungs that is becoming a major health issue in many industrialized countries. Yet the molecular mechanisms that contribute to asthma pathogenesis are not well understood. Analysis of the relevance of asthma susceptibility genes may lead to a better understanding of the pathogenic mechanisms that cause this disease. In this study we analyzed the asthma susceptibility gene ORMDL3 using the model organism Drosophila melanogaster. ORMDL3 is an ER transmembrane protein whose functions have not been thoroughly elucidated. Thus, this study aimed to determine the functions of ORMDL3 and role of ORMDL3 in asthma pathogenesis.

We could show that an increased ORMDL (sole Drosophila homologue of human ORMDL1–3) expression in Drosophila airways enhances the susceptibility to hypoxia. This phenotype was accompanied by an enhanced phosphorylation of the c-Jun N-terminal kinase (JNK), suggesting a role of this stress responsive kinase in the molecular basis of the increased susceptibility.

To study the molecular changes induced by ORMDL, we performed microarray experiments and analyzed the phospholipid composition using mass spectrometry. Our data indicate a role of ORMDL in epithelial renewal processes and show a reduction of ceramides in Drosophila guts by a deregulation of ORMDL.

Taken together, our data suggest that a deregulation of the asthma susceptibility gene ORMDL leads to an enhanced susceptibility to stress which is supposedly based on altered ceramide levels and/or impaired repair mechanisms.