Key result
Reduction of G6PD and other NADPH-producing enzymes suppressed the cardiomyopathy and eye phenotypes caused by the human CryABR120G mutation in a Drosophila model, linking the pathology to reductive stress.
Reducing NADPH production via metabolic network enzymes suppresses cardiomyopathy pathology in a Drosophila model of CryAB(R120G) mutation, highlighting reductive stress as a potential therapeutic target.
Reductive stress may be a therapeutic target in CryAB cardiomyopathy; Drosophila data leave open human translation.
Dominant mutations in the alpha-B crystallin (CryAB) gene are responsible for a number of inherited human disorders, including cardiomyopathy, skeletal muscle myopathy, and cataracts. The cellular mechanisms of disease pathology for these disorders are not well understood. Among recent advances is that the disease state can be linked to a disturbance in the oxidation/reduction environment of the cell. In a mouse model, cardiomyopathy caused by the dominant CryAB(R120G) missense mutation was suppressed by mutation of the gene that encodes glucose 6-phosphate dehydrogenase (G6PD), one of the cell's primary sources of reducing equivalents in the form of NADPH. Here, we report the development of a Drosophila model for cellular dysfunction caused by this CryAB mutation. With this model, we confirmed the link between G6PD and mutant CryAB pathology by finding that reduction of G6PD expression suppressed the phenotype while overexpression enhanced it. Moreover, we find that expression of mutant CryAB in the Drosophila heart impaired cardiac function and increased heart tube dimensions, similar to the effects produced in mice and humans, and that reduction of G6PD ameliorated these effects. Finally, to determine whether CryAB pathology responds generally to NADPH levels we tested mutants or RNAi-mediated knockdowns of phosphogluconate dehydrogenase (PGD), isocitrate dehydrogenase (IDH), and malic enzyme (MEN), the other major enzymatic sources of NADPH, and we found that all are capable of suppressing CryAB(R120G) pathology, confirming the link between NADP/H metabolism and CryAB.
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Xie et al. (2013) studied CryABR120G cardiomyopathy and reductive stress. Reduction of G6PD and other NADPH-producing enzymes vs. Unmanipulated CryABR120G expression was evaluated on Cardiac function (fractional shortening, heart period, diameters) and eye phenotype. Reduction of G6PD and other NADPH-producing enzymes suppressed the cardiomyopathy and eye phenotypes caused by the human CryABR120G mutation in a Drosophila model, linking the pathology to reductive stress.
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