Patient-derived phosphoribosyl pyrophosphate synthetase mutations in Drosophila result in autophagy and lysosome dysfunction

Phosphoribosyl pyrophosphate synthetase (PRPS) is a rate-limiting enzyme in nucleotide metabolism. While missense mutations of PRPS1 have been identified in neurological disorders such as Arts syndrome, little is known on how they contribute to pathogenesis. We engineered Drosophila PRPS (dPRPS) alleles that carry patient-derived PRPS missense mutations. Although dPRPS mutant flies develop normally, they have profound defects in autophagy induction and lysosome function. Consequently, dPRPS flies are sensitive to nutrient deprivation as they are unable to break down lipid storage by macroautophagy. In addition, we provide evidence showing that dRPPS is required for proper cellular response to oxidative stress, providing a possible mechanism by which PRPS1 dysfunction contributes to neurological disorders.