Functional characterization of PREPL and the role in Prader-Willi syndrome

This PhD project will contribute to the elucidation of the functional role of prolyl endopeptidase-like. Inactivation of PREPL results in neonatal hypotonia, growth hormone deficiency  and feeding problems. The regulated secretion pathway is disturbed in PREPL deficient patients, somatotrophs of PREPL KO mice and in PREPL knockdown neuroendocrine cells. Also, since PREPL interacts with AP-1, which is essential for biogenesis and maturation of secretion vesicles, we can suggest that PREPL is involved in regulated secretion. Furthermore, this interaction results in an increased membrane dissociation of AP-1. Therefore we hypothesize that PREPL has a phospholipase activity.

Unravelling the molecular mechanisms of PREPL can contribute to a treatment that can improve the quality of life of the patients. Therefore,  we will perform competition experiments and look into the interactions of PREPL and PI-4-P. Additionally, secretion studies and morphometric and biochemical analysis of the secretory vesicles will be performed to reveal the role of PREPL in regulated secretion.

These findings are complemented by the results of Luc Régal (PhD: The role of PREPL in the hypotonia-cystinuria syndrome). The focus is on the clinical aspect, with the identification of PREPL deficient patients and the clinical study for the treatment of hypotonia.