PRPS-Associated Disorders and the Drosophila Model of Arts Syndrome

Abstract

<jats:p>While a plethora of genetic techniques have been developed over the past century, modifying specific sequences of the fruit fly genome has been a difficult, if not impossible task. clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 truly redefined molecular genetics and provided new tools to model human diseases in Drosophila melanogaster. This is particularly true for genes whose protein sequences are highly conserved. Phosphoribosyl pyrophosphate synthetase (PRPS) is a rate-limiting enzyme in nucleotide metabolism whose missense mutations are found in several neurological disorders, including Arts syndrome. In addition, PRPS is deregulated in cancer, particularly those that become resistant to cancer therapy. Notably, Drosophila PRPS shares about 90% protein sequence identity with its human orthologs, making it an ideal gene to study via CRISPR/Cas9. In this review, we will summarize recent findings on PRPS mutations in human diseases including cancer and on the molecular mechanisms by which PRPS activity is regulated. We will also discuss potential applications of Drosophila CRISPR/Cas9 to model PRPS-dependent disorders and other metabolic diseases that are associated with nucleotide metabolism.</jats:p>

Inborn Errors of Purine Salvage and Catabolism

“…Drosophila PRPS shares about 90% protein sequence identity with its human homologs and was also used as a model. By engineering patient-derived missense mutations in Drosophila , Delos Santos et al [ 29 ] found some enzyme activity, supporting the hypothesis that enzyme function was not completely eliminated in human patients. The above Drosophila model showed macroautophagic/lysosomal defects, not yet investigated in patients, which were suggested to contribute to PRPS-associated neuropathology and could be partially improved by a SAM-enriched diet [ 29 ].…”

“…By engineering patient-derived missense mutations in Drosophila , Delos Santos et al [ 29 ] found some enzyme activity, supporting the hypothesis that enzyme function was not completely eliminated in human patients. The above Drosophila model showed macroautophagic/lysosomal defects, not yet investigated in patients, which were suggested to contribute to PRPS-associated neuropathology and could be partially improved by a SAM-enriched diet [ 29 ]. De Brouwer et al [ 33 ] hypothesized that the symptoms observed in Arts syndrome may be the result of nucleotide depletion in energy-requiring key tissues, and that the demyelination found in the CNS of one Arts patient at autopsy might be the result of a reduction in pyrimidine nucleotides, essential for membrane and myelin synthesis through their lipid esters.…”

“…The loss-of-function mutations in PRPS1 , identified as missense up to now, may result in destabilizing the ATP binding sites and disturbing the allosteric sites. Likely due to the essential role of PRPS1 in nucleotide metabolism for embryonic development, that supposedly neither PRPS2 nor PRPS1L1 can compensate, the mutant form of PRPS1 retains some activity that allows affected individuals to complete embryonic and fetal development [ 29 ]. PRPS deficiency causes rare X-linked diseases, although females exhibiting a severe disease phenotype have been reported [ 30 ].…”

Direct stimulation of de novo nucleotide synthesis by O-GlcNAcylation

“…PRPS1 uninhibitable activation also results in thiopurine resistance in relapsed childhood ALL 17 . Decreased PRPS1 activity is also linked to disorders such as Arts syndrome and retinal dystrophy 18 , whereas its superactivity is accountable for neurosensory deficits, hyperuricemia and gouty arthritis 19 , 20 .…”

“…Cancer cells exhibit abnormal glucose metabolism and aberrant O-GlcNAcylation level, implying that the flux through the HBP may be altered 21,23,26,35 . On the other hand, cancer cells have reprogrammed dystrophy 18 , whereas its superactivity is accountable for neurosensory deficits, hyperuricemia and gouty arthritis 19,20 .…”