Removal of prolyl oligopeptidase reduces alpha-synuclein toxicity in cells and in vivo

• Published in: Scientific reports Vol. 8; no. 1; pp. 1552 - 18
• Main Authors: Svarcbahs, Reinis, Julku, Ulrika H., Norrbacka, Susanna, Myöhänen, Timo T.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24-01-2018; Nature Publishing Group
• Subjects: 13/109; 13/51; 631/378/1689/1718; 631/378/340; 64/110; 64/60; 692/617/375/1718; 82/80; 96/63; alpha-Synuclein - toxicity; Animal behavior; Animals; Autophagy; Behavior, Animal; Chromatography, High Pressure Liquid; Disease Models, Animal; Dopamine; Dopamine - analysis; Dopamine receptors; Dopaminergic Neurons - pathology; Endopeptidase K; High-performance liquid chromatography; Humanities and Social Sciences; Hydroxylase; Immunohistochemistry; Liquid chromatography; Locomotion; Locomotor activity; Metabolites; Mice; Mice, Knockout; Microdialysis; multidisciplinary; Oligopeptidase; Parkinson Disease - physiopathology; Parkinson's disease; Phagocytosis; Prolyl oligopeptidase; Prolyl Oligopeptidases; Proteasome Endopeptidase Complex - metabolism; Proteasomes; Proteinase; Science; Science (multidisciplinary); Serine Endopeptidases - deficiency; Serine Endopeptidases - metabolism; Synuclein; Toxicity; Tyrosine 3-monooxygenase
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-19823-y

Prolyl oligopeptidase (PREP) inhibition by small-molecule inhibitors can reduce alpha-synuclein (aSyn) aggregation, a key player in Parkinson’s disease pathology. However, the significance of PREP protein for aSyn aggregation and toxicity is not known. We studied this
in vivo
by using PREP knock-out mice with viral vector injections of aSyn and PREP. Animal behavior was studied by locomotor activity and cylinder tests, microdialysis and HPLC were used to analyze dopamine levels, and different aSyn forms and loss of dopaminergic neurons were studied by immunostainings. Additionally, PREP knock-out cells were used to characterize the impact of PREP and aSyn on autophagy, proteasomal system and aSyn secretion. PREP knock-out animals were nonresponsive to aSyn-induced unilateral toxicity but combination of PREP and aSyn injections increased aSyn toxicity. Phosphorylated p129, proteinase K resistant aSyn levels and tyrosine hydroxylase positive cells were decreased in aSyn and PREP injected knock-out animals. These changes were accompanied by altered dopamine metabolite levels. PREP knock-out cells showed reduced response to aSyn, while cells were restored to wild-type cell levels after PREP overexpression. Taken together, our data suggests that PREP can enhance aSyn toxicity
in vivo
.