Prolyl oligopeptidase inhibition attenuates the toxicity of a proteasomal inhibitor, lactacystin, in the alpha-synuclein overexpressing cell culture

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Myöhänen , T T , Norrbacka , S & Savolainen , M H 2017 , ' Prolyl oligopeptidase inhibition attenuates the toxicity of a proteasomal inhibitor, lactacystin, in the alpha-synuclein overexpressing cell culture ' , Neuroscience Letters , vol. 636 , pp. 83-89 . https://doi.org/10.1016/j.neulet.2016.11.008

Title: Prolyl oligopeptidase inhibition attenuates the toxicity of a proteasomal inhibitor, lactacystin, in the alpha-synuclein overexpressing cell culture
Author: Myöhänen, Timo T.; Norrbacka, Susanna; Savolainen, Mari H.
Contributor organization: Faculty of Pharmacy
Division of Pharmacology and Pharmacotherapy
Regenerative pharmacology group
Drug Research Program
PREP in neurodegenerative disorders
Date: 2017-01-01
Language: eng
Number of pages: 7
Belongs to series: Neuroscience Letters
ISSN: 0304-3940
DOI: https://doi.org/10.1016/j.neulet.2016.11.008
URI: http://hdl.handle.net/10138/307680
Abstract: Lewy bodies, the histopathological hallmarks of Parkinson's disease (PD), contain insoluble and aggregated alpha-synuclein (aSyn) and many other proteins, proposing a role for failure in protein degradation system in the PD pathogenesis. Proteasomal dysfunction has indeed been linked to PD and aSyn oligomers have been shown to inhibit proteasomes and autophagy. Our recent studies have shown that inhibitors of prolyl oligopeptidase (PREP) can prevent the aggregation and enhance the clearance of accumulated aSyn, and therefore, we wanted to study if PREP inhibition can overcome the aSyn aggregation and toxicity induced by lactacystin, a proteasomal inhibitor. The cells overexpressing human A30P or A53T mutated aSyn were incubated with lactacystin and a PREP inhibitor, KYP-2047, for 48 h. Theafter, the cells were fractioned, and the effects of lactacystin with/without 1 mu M KYP-2047 on aSyn aggregation and ubiquitin accumulation, cell viability and on autophagic markers (p62, Beclin1 and LC3BII) were studied. We found that KYP-2047 attenuated lactacystin-induced cell death in mutant aSyn overexpressing cells but not in non-overexpressing control cells. KYP-2047 reduced significantly SDS-insoluble high-molecular-weight aSyn oligomers that were in line with the cell viability results. In addition, significant reduction in protein accumulation marker, p62, was seen in SDS fraction while LC3BII, a marker for autophagosome formation, was increased, indicating to enhanced autophagy. Our results further streghten the possibilities for PREP inhibitors as a potential drug therapy against synucleinopathies and other protein aggregating diseases. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
Subject: Serine protease
Parkinson's disease
Synucleinopathies
Alpha-synuclein aggregation
Enzyme inhibition
PARKINSONS-DISEASE
PROTEIN
AUTOPHAGY
AGGREGATION
MICE
DEGRADATION
PATHOLOGY
KYP-2047
LEADS
PC12
3112 Neurosciences
317 Pharmacy
Peer reviewed: Yes
Rights: cc_by_nc_nd
Usage restriction: openAccess
Self-archived version: acceptedVersion


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