Intersection of fragile X syndrome and glycogen storage disease models in metabolic neuromuscular junction requirements

A classic human patient comorbidity of Fragile X syndrome (FXS) and Glycogen Storage Disease Type IX (GSD) has symptoms far more severe than either single disease alone. Causal mutations result in loss of the translational regulator Fragile X Ribonucleoprotein 1 (FMRP) and metabolic regulator Phosphorylase Kinase Regulatory Subunit Alpha 2 (PHKA2), respectively. We hypothesized FMRP-PHKA2 interaction from unsustainably elevated metabolic demand. In Drosophila disease models, single null mutants are viable, but double knockout (DKO) animals exhibit 100% synthetic lethality, showing an essential interaction. Metabolically, dFMRP and dPHKA2 loss alone causes opposing changes in glycogen and fat stores, but DKO animals return both energy stores to normal. Regulatory Fat Body Protein-1 is elevated in single disease models, but likewise returned to normal in the DKO animals. In tests of neurological phenotypes, neuromuscular junction (NMJ) mitochondrial function, synapse architecture, and neurotransmission strength are all elevated by dFMRP loss, but these synaptic properties are restored to normal levels by co-removal of dPHKA2 in DKO animals. Thus, dFMRP and dPHKA2 strongly interact in metabolic and neuromuscular mechanisms, without explaining the DKO lethal interaction.