Monosaccharides improve symptoms of an animal model for type III galactosemia, through the activation of the insulin pathway

Abstract

Type III galactosemia is characterized by the inability to metabolize galactose due to deficiency of the UDP-galactose-4-epimerase (GALE) gene, which catalyzes the interconversion of UDP-Galactose and UDP-Glucose. Additionally, GALE interconverts UDP-N-Acetylgalactosamine and UDP-N-Acetylglucosamine. These four sugars are needed for glycosylation of biomolecules. GALE deletion is considered lethal, and all described patients carry hypomorphic mutations. Symptoms are diverse and can range from mild to severe, without effective treatment. We have previously generated a Caenorhabditis elegans model for type III galactosemia, which carries a hypomorphic mutation in the GALE gene homologue. In this model, we observed that the symptoms varied depending on the diet. The aim of this work is to identify which dietary metabolites might alleviate the symptoms of type III galactosemia. To identify the molecules responsible, we used a C. elegans model of type III galactosemia and a mouse model to test whether the respond to the treatment is conserved in mammals and thus could be a putative intervention in patients.

We found that high levels of monosaccharides in the diet is responsible for the beneficial effect in the C. elegans model. This intervention generates an increase of gale-1 expression through activation of the insulin pathway which may explain the reduction of the symptoms in animals carrying hypomorphic mutations. The increase of the GALE gene expression after monosaccharides treatment is also conserved in mammals and if maintained in humans, monosaccharide treatment combined with monitorization of GALE expression could be included in the management of patients with type III galactosemia.