Prolyl oligopeptidase inhibition reduces alpha‐synuclein aggregation in a cellular model of multiple system atrophy

• Published in: Journal of cellular and molecular medicine Vol. 25; no. 20; pp. 9634 - 9646
• Main Authors: Cui, Hengjing, Kilpeläinen, Tommi, Zouzoula, Lydia, Auno, Samuli, Trontti, Kalevi, Kurvonen, Sampo, Norrbacka, Susanna, Hovatta, Iiris, Jensen, Poul Henning, Myöhänen, Timo T.
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01-10-2021; John Wiley and Sons Inc
• Subjects: alpha-Synuclein - metabolism; alpha‐synuclein; Animal models; Antibodies; Atrophy; Autophagy; Cell culture; Cell death; Cell Line; Cell Survival; Cell viability; Cytosol; Dementia; Experiments; Humans; Inclusion bodies; KYP‐2047; Laboratories; mRNA; multiple system atrophy; Multiple System Atrophy - drug therapy; Multiple System Atrophy - etiology; Multiple System Atrophy - metabolism; Multiple System Atrophy - pathology; Nerve Tissue Proteins - metabolism; neurodegeneration; Neurodegenerative diseases; Neuronal-glial interactions; Oligodendrocytes; Oligodendroglia - metabolism; Oligodendroglia - pathology; Oligopeptidase; Original; Parkinson's disease; Penicillin; Phagocytosis; Phosphoprotein phosphatase; Phosphorylation; Prolyl oligopeptidase; Prolyl Oligopeptidases - antagonists & inhibitors; Protein Aggregates - drug effects; Protein Aggregation, Pathological - drug therapy; Protein Aggregation, Pathological - metabolism; Protein phosphatase; Proteins; Sheep; Synuclein; synucleinopathies; Toxicity; Transfection; Tubulin; neurodegeneration; multiple system atrophy; KYP-2047; prolyl oligopeptidase; alpha-synuclein; synucleinopathies
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.16910

Multiple system atrophy (MSA) is a fatal neurodegenerative disease where the histopathological hallmark is glial cytoplasmic inclusions in oligodendrocytes, rich of aggregated alpha‐synuclein (aSyn). Therefore, therapies targeting aSyn aggregation and toxicity have been studied as a possible disease‐modifying therapy for MSA. Our earlier studies show that inhibition of prolyl oligopeptidase (PREP) with KYP‐2047 reduces aSyn aggregates in several models. Here, we tested the effects of KYP‐2047 on a MSA cellular models, using rat OLN‐AS7 and human MO3.13 oligodendrocyte cells. As translocation of p25α to cell cytosol has been identified as an inducer of aSyn aggregation in MSA models, the cells were transiently transfected with p25α. Similar to earlier studies, p25α increased aSyn phosphorylation and aggregation, and caused tubulin retraction and impaired autophagy in OLN‐AS7 cells. In both cellular models, p25α transfection increased significantly aSyn mRNA levels and also increased the levels of inactive protein phosphatase 2A (PP2A). However, aSyn or p25α did not cause any cellular death in MO3.13 cells, questioning their use as a MSA model. Simultaneous administration of 10 µM KYP‐2047 improved cell viability, decreased insoluble phosphorylated aSyn and normalized autophagy in OLN‐AS7 cells but similar impact was not seen in MO3.13 cells.