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

Hengjing Cui, Tommi Kilpeläinen, Lydia Zouzoula, Samuli Auno, Kalevi Trontti, Sampo Kurvonen, Susanna Norrbacka, Iiris Hovatta, Poul Henning Jensen, Timo T. Myöhänen (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

7 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)9634-9646
Number of pages13
JournalJournal of Cellular and Molecular Medicine
Volume25
Issue number20
DOIs
Publication statusPublished - Oct 2021
MoE publication typeA1 Journal article-refereed

Keywords

  • alpha-synuclein
  • KYP-2047
  • multiple system atrophy
  • neurodegeneration
  • prolyl oligopeptidase
  • synucleinopathies

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