Exploring metabolic pathways that link Congenital Myasthenic Syndrome-22, caused by PREPL deficiency to Prader-Willi Syndrome

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. Creemers Lab has recently found that PREPL can be inhibited by a palmitoyl-protein thioesterase inhibitor and can cleave synthetic (thio)esterase substrates. Furthermore, their preliminary results show a downregulation of PCSK1 and NHLH2 in hypothalami of PREPL KO mice. The latter is similar to a recent study in a PWS mouse model and induced pluripotent stem cell-derived neurons of PWS patients. Finally, they serendipitously discovered a therapeutic effect on hypotonia in PREPL null patients using the antibiotic trimethoprim-sulfamethoxazole and 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. We hypothesize that these are palmitoylated proteins, some of which are involved in regulating mitochondrial function. 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, the lab has already shown that one of the metabolites of trimethoprim can activate α1A adrenergic receptors.