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Last update 08 May 2025

PREPL

Last update 08 May 2025

Basic Info

Synonyms

KIAA0436, PREPL, prolyl endopeptidase like

+ [2]

Introduction

Serine peptidase whose precise substrate specificity remains unclear (PubMed:16143824, PubMed:16385448, PubMed:28726805). Does not cleave peptides after a arginine or lysine residue (PubMed:16143824). Regulates trans-Golgi network morphology and sorting by regulating the membrane binding of the AP-1 complex (PubMed:23321636). May play a role in the regulation of synaptic vesicle exocytosis (PubMed:24610330).

Drugs associated with PREPL

ACT-02

Target

PREPL

Mechanism

PREPL inhibitors

Active Org.

Bionure Farma SL [+1]

Originator Org.

Bionure Farma SL

Active Indication

Parkinson Disease

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

JTP-4819

Target

PREPL

Mechanism

PREPL inhibitors

Active Org.-

Originator Org.

Japan Tobacco (Hong Kong) Ltd.

Active Indication-

Inactive Indication

Cognition Disorders

Drug Highest PhaseDiscontinued

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

SUAM-1221

Target

PREPL

Mechanism

PREPL inhibitors

Active Org.-

Originator Org.

Chinoin Zrt.

Active Indication-

Inactive Indication

Amnesia

Drug Highest PhaseDiscontinued

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with PREPL

100 Translational Medicine associated with PREPL

0 Patents (Medical) associated with PREPL

Literatures (Medical) associated with PREPL

10 Sep 2024·JCI Insight

Missense variants in CMS22 patients reveal that PREPL has both enzymatic and nonenzymatic functions

Article

Author: Agostinis, Patrizia ; Rosier, Karen ; Vanhoutte, Roeland ; Lee, Jennifer A ; Meulemans, Sandra ; Dal Peraro, Matteo ; Schroer, Richard J ; Spellicy, Catherine J ; Marcaida, Maria J ; Bhalla, Kritika ; Mahy, Alexia ; Cavani, Edoardo ; Maselli, Ricardo A ; Antanasijevic, Aleksandar ; Monnens, Yenthe ; Rochtus, Anne ; Lemmens, Irma ; Pagliarini, David J ; Theodoropoulou, Anastasia ; Creemers, John Wm ; Laverty, Chamindra G ; Verhelst, Steven

Congenital myasthenic syndrome-22 (CMS22, OMIM 616224) is a rare genetic disorder caused by deleterious genetic variation in the prolyl endopeptidase-like (PREPL) gene. Previous reports have described patients with deletions and nonsense variants in PREPL, but nothing is known about the effect of missense variants in the pathology of CMS22. In this study, we have functionally characterized missense variants in PREPL from 3 patients with CMS22, all with hallmark phenotypes. Biochemical evaluation revealed that these missense variants do not impair hydrolase activity, thereby challenging the conventional diagnostic criteria and disease mechanism. Structural analysis showed that the variants affect regions most likely involved in intraprotein or protein-protein interactions. Indeed, binding to a selected group of known interactors was differentially reduced for the 3 variants. The importance of nonhydrolytic functions of PREPL was investigated in catalytically inactive PREPL p.Ser559Ala cell lines, which showed that hydrolytic activity of PREPL is needed for normal mitochondrial function but not for regulating AP1-mediated transport in the transgolgi network. In conclusion, these studies showed that CMS22 can be caused not only by deletion and truncation of PREPL but also by missense variants that do not necessarily result in a loss of hydrolytic activity of PREPL.

01 Sep 2024·Pediatric Neurology

Congenital Myasthenic Syndromes in Belgium: Genetic and Clinical Characterization of Pediatric and Adult Patients

Article

Author: Van Parijs, Vinciane ; Herdewyn, Sarah ; Dubuisson, Nicolas ; Paquay, Stéphanie ; De Bleecker, Jan ; Smeets, Nathalie ; Gheldof, Alexander ; Deconinck, Nicolas ; Remiche, Gauthier ; Vanlander, Arnaud ; Dequeker, Bart ; Bissay, Véronique ; Maldonado Slootjes, Sofia ; Dontaine, Pauline ; Alonso-Jimenez, Alicia ; Hansen, Isabelle ; De Waele, Liesbeth ; De Ridder, Willem ; Claeys, Kristl G ; Peirens, Geertrui ; Seneca, Sara ; Régal, Luc ; Beysen, Diane ; Poleur, Margaux

BACKGROUNDCongenital myasthenic syndromes (CMS) are a group of genetic disorders characterized by impaired neuromuscular transmission. CMS typically present at a young age with fatigable muscle weakness, often with an abnormal response after repetitive nerve stimulation (RNS). Pharmacologic treatment can improve symptoms, depending on the underlying defect. Prevalence is likely underestimated. This study reports on patients with CMS followed in Belgium in 2022.METHODSData were gathered retrospectively from the medical charts. Only likely pathogenic and pathogenic variants were included in the analysis.RESULTSWe identified 37 patients, resulting in an estimated prevalence of 3.19 per 1,000,000. The patients harbored pathogenic variants in CHRNE, RAPSN, DOK7, PREPL, CHRNB1, CHRNG, COLQ, MUSK, CHRND, GFPT1, and GMPPB. CHRNE was the most commonly affected gene. Most patients showed disease onset at birth, during infancy, or during childhood. Symptom onset was at adult age in seven patients, caused by variants in CHRNE, DOK7, MUSK, CHRND, and GMPPB. Severity and distribution of weakness varied, as did the presence of respiratory involvement, feeding problems, and extraneuromuscular manifestations. RNS was performed in 23 patients of whom 18 demonstrated a pathologic decrement. Most treatment responses were predictable based on the genotype.CONCLUSIONSThis is the first pooled characterization of patients with CMS in Belgium. We broaden the phenotypical spectrum of pathogenic variants in CHRNE with adult-onset CMS. Systematically documenting larger cohorts of patients with CMS can aid in better clinical characterization and earlier recognition of this rare disease. We emphasize the importance of establishing a molecular genetic diagnosis to tailor treatment choices.

01 Jun 2024·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

Similar metabolic pathways are affected in both Congenital Myasthenic Syndrome-22 and Prader-Willi Syndrome

Article

Author: Rochtus, Anne ; Rosier, Karen ; Thorrez, Lieven ; Monnens, Yenthe ; Creemers, John W M ; Meier, Daniel T ; Meulemans, Sandra ; Resnick, James L ; Agostinis, Patrizia ; Vervoort, Ellen ; Bhalla, Kritika

Loss of prolyl endopeptidase-like (PREPL) encoding a serine hydrolase with (thio)esterase activity leads to the recessive metabolic disorder Congenital Myasthenic Syndrome-22 (CMS22). It is characterized by severe neonatal hypotonia, feeding problems, growth retardation, and hyperphagia leading to rapid weight gain later in childhood. The phenotypic similarities with Prader-Willi syndrome (PWS) are striking, suggesting that similar pathways are affected. The aim of this study was to identify changes in the hypothalamic-pituitary axis in mouse models for both disorders and to examine mitochondrial function in skin fibroblasts of patients and knockout cell lines. We have demonstrated that Prepl is downregulated in the brains of neonatal PWS-IC^-p/+m mice. In addition, the hypothalamic-pituitary axis is similarly affected in both Prepl^-/- and PWS-IC^-p/+m mice resulting in defective orexigenic signaling and growth retardation. Furthermore, we demonstrated that mitochondrial function is altered in PREPL knockout HEK293T cells and can be rescued with the supplementation of coenzyme Q10. Finally, PREPL-deficient and PWS patient skin fibroblasts display defective mitochondrial bioenergetics. The mitochondrial dysfunction in PWS fibroblasts can be rescued by overexpression of PREPL. In conclusion, we provide the first molecular parallels between CMS22 and PWS, raising the possibility that PREPL substrates might become therapeutic targets for treating both disorders.

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