PREPL, a serine hydrolase deleted in patients with a Prader Willi-like syndrome; functional characterization and exploration of novel therapeutic avenues

Inactivation of PREPL (PRolyl EndoPeptidase-Like) causes a recessive disease similar to Prader-Willi syndrome (PWS) and is characterized by neonatal hypotonia, growth deficiency, feeding problems, and mild cognitive delay. How PREPL deficiency causes these pathologies is currently unknown.

We have recently found that PREPL can be inhibited by a palmitoyl-protein thioesterase inhibitor and can cleave synthetic (thio)esterase substrates. Furthermore, our preliminary results show a downregulation of PCSK1 and NHLH2 in hypothalami of PREPL KO mice. This is similar to a recent study in a PWS mouse model and induced pluripotent stem cell-derived neurons of PWS patients. Finally, we serendipitously discovered a therapeutic effect on hypotonia in PREPL null patients using the antibiotic trimethoprim-sulfamethoxazole and we excluded sulfamethoxazole as the cause in a small clinical trial.

The aim of this research is to identify the physiological substrates of PREPL relevant for the phenotype observed in the PREPL deficient patients, which we predict to be palmitoylated proteins. In addition, we will explore molecular links between PREPL deficiency and PWS. Furthermore, we will characterize the mode of action of trimethoprim. In a pilot study, we have shown that one of the metabolites of trimethoprim can activate α1A adrenergic receptors.