Nuevo ligando de PREP, HUP-46, mejora los déficits conductuales en un modelo de la enfermedad de Parkinson basado en...

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, and current therapies cannot stop or delay the neuronal death. Therefore, novel therapies having disease-modifying effects are urgently needed. Small-molecular ligands for prolyl oligopeptidase (PREP) have shown disease-modifying effects in various α-synuclein (aSyn) based PD mouse models. We have recently developed novel, more effective PREP ligand series that aim to regulate PREP-related protein-protein interactions, such as with aSyn and protein phosphatase 2 A (PP2A). The most promising novel PREP ligand, HUP-46, was now tested in a PD mouse model based on unilateral AAV-A53T-aSyn virus vector injection on substantia nigra. Our results show that HUP-46, but not reference PREP inhibitor, KYP-2047, was able to restore the behavioral deficit caused by the virus vector injection in the cylinder test. 4-week treatment with PREP ligands reduced the soluble and insoluble aSyn oligomers, and iNOS-positive microglial cells in the substantia nigra. When the effect on microglial activity was further studied in the BV2 microglial cell culture activated by lipopolysaccharide and interferon-γ, the results revealed that HUP-46 but not KYP-2047 significantly reduced TNF-α production. Analysis revealed that HUP-46 reduced p38 phosphorylation and restored autophagic flux in the activated BV2 cells that may contribute to the reduced pro-inflammatory activation of BV2 cells. Taken together, our results suggest that novel PREP ligands, such as HUP-46, can have disease-modifying effect on PD mouse model.