Prolyl oligopeptidase inhibition reduces alpha-synuclein aggregation in a cellular model of multiple system atrophy.
Cell Line
Cell Survival
Humans
Multiple System Atrophy
/ drug therapy
Nerve Tissue Proteins
/ metabolism
Oligodendroglia
/ metabolism
Phosphorylation
Prolyl Oligopeptidases
/ antagonists & inhibitors
Protein Aggregates
/ drug effects
Protein Aggregation, Pathological
/ drug therapy
alpha-Synuclein
/ metabolism
KYP-2047
alpha-synuclein
multiple system atrophy
neurodegeneration
prolyl oligopeptidase
synucleinopathies
Journal
Journal of cellular and molecular medicine
ISSN: 1582-4934
Titre abrégé: J Cell Mol Med
Pays: England
ID NLM: 101083777
Informations de publication
Date de publication:
10 2021
10 2021
Historique:
revised:
19
08
2021
received:
15
01
2021
accepted:
23
08
2021
pubmed:
7
9
2021
medline:
26
2
2022
entrez:
6
9
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34486218
doi: 10.1111/jcmm.16910
pmc: PMC8505845
doi:
Substances chimiques
Nerve Tissue Proteins
0
Protein Aggregates
0
TPPP protein, human
0
alpha-Synuclein
0
Prolyl Oligopeptidases
EC 3.4.21.26
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
9634-9646Informations de copyright
© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.
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