Abstract
Phosphoribosyl pyrophosphate synthetase (PRPS) is a rate-limiting enzyme whose function is important for the biosynthesis of purines, pyrimidines, and pyridines. Importantly, while missense mutations of PRPS1 have been identified in neurological disorders such as Arts syndrome, how they contribute to neuropathogenesis is still unclear. We identified the Drosophila ortholog of PRPS (dPRPS) as a direct target of RB/E2F in Drosophila, a vital cell cycle regulator, and engineered dPRPS alleles carrying patient-derived mutations. Interestingly, while they are able to develop normally, dPRPS mutant flies have a shortened lifespan and locomotive defects, common phenotypes associated with neurodegeneration. Careful analysis of the fat body revealed that patient-derived PRPS mutations result in profound defects in lipolysis, macroautophagy, and lysosome function. Significantly, we show evidence that the nervous system of dPRPS mutant flies is affected by these defects. Overall, we uncovered an unexpected link between nucleotide metabolism and autophagy/lysosome function, providing a possible mechanism by which PRPS-dysfunction contributes to neurological disorders.
Highlights
Phosphoribosyl pyrophosphate synthetase (PRPS) is a rate-limiting enzyme in the biosynthesis of purine, pyrimidine, and, pyridine nucleotides (Fig 1A)
While PRPS is mutated in neurological disorders such as Arts syndrome, CharcotMarie-Tooth disease, and nonsyndromic sensorineural deafness, it is currently unclear why PRPS dysfunction leads to neurological disorders
We engineered a Drosophila model of ARTS syndrome and discovered that PRPS mutations result in defects in lysosome-mediated and autophagy processes, which are known to be important for neuronal homeostasis
Summary
Phosphoribosyl pyrophosphate synthetase (PRPS) is a rate-limiting enzyme in the biosynthesis of purine, pyrimidine, and, pyridine nucleotides (Fig 1A). Knockout mutants of PRPS orthologs have been generated in a number of animal models. PRPS1 knockout mice were generated as a part of a high-throughput screening of mouse genes important for skeletal muscle development [4]. PRPS1 was identified as an X-linked gene required for animal viability, supporting the notion that the gene is essential for embryonic development. PRPS2 knockout mice are viable and fertile with no discernable developmental defects. This suggests that other mouse PRPS orthologs, PRPS1 and PRPS1L1, can compensate for the loss of PRPS2 [5]. The mutant animals of the two zebrafish PRPS orthologs, PRPS1a and PRPS1b, fail to properly develop and show some phenotypic similarities to human PRPS1-associated diseases. Only null alleles of PRPS were generated in both mouse and zebrafish models and the biological consequence of patient-derived PRPS1 mutations have not been directly examined
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