Functional characterization of PREPL, a serine hydrolase deleted in patients with a Prader Willi-like syndrome, and evaluation of new medication for the treatment of myasthenia

Inactivation of PREPL (PRolyl EndoPeptidase-Like) causes a recessive disease characterized by neonatal hypotonia, growth deficiency, feeding problems, and mild cognitive delay. How PREPL deficiency causes these pathologies is currently unknown. Recently, we discovered that hypotonia in PREPL deficient patients is caused by a defect in neuromuscular transmission. In vitro and ex vivo studies have shown that regulated secretion is also disturbed in neuroendocrine cells.Recently, we made the serendipitous observation that the side-effect of a certain medication greatly improves the hypotonia. This is currently being evaluated in a clinical trial. We have also made an inhibitor profile for serine hydrolases, which suggest that PREPL is probably not an endopeptidase like its homologue PREP, but an esterase.In this project, we will further examine the side-effect of the medication in ex vivo systems and in cell lines. Furthermore, the catalytic activity will be determined. Finally, the affected pathways and sy naptic function will be examined.

Keywords:myasthenia

Disciplines:Genetics, Systems biology, Molecular and cell biology