Browsing by Subject "Synucleinopathies"
Now showing items 1-4 of 4
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(2022)• Parkinsonin tautiin liittyy laaja-alaisia vaurioita keskushermostossa sekä autonomisessa ja enteerisessä hermostossa. • Taudin taustalla on alfasynukleiinin poikkeava laskostuminen ja aggregaatio. • Ummetus kuuluu taudin varhaisimpiin oireisiin. Se voi ilmaantua vuosia ennen motorisia oireita. • Osalla potilaista taudin patogeneesi saattaa saada alkunsa suolistossa ja levitä sieltä kohti keskushermostoa. • Ylemmän ruoansulatuskanavan toiminnalla on merkitystä levodopan imeytymiselle.
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(2017)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.
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(2020)Growing evidence emphasizes insufficient clearance of pathological alpha-synuclein (alpha SYN) aggregates in the progression of Parkinson's disease (PD). Consequently, cellular degradation pathways represent a potential therapeutic target. Prolyl oligopeptidase (PREP) is highly expressed in the brain and has been suggested to increase alpha SYN aggregation and negatively regulate the autophagy pathway. Inhibition of PREP with a small molecule inhibitor, KYP-2407, stimulates autophagy and reduces the oligomeric species of alpha SYN aggregates in PD mouse models. However, whether PREP inhibition has any effects on intracellular alpha SYN fibrils has not been studied before. In this study, the effect of KYP2407 on alpha SYN preformed fibrils (PFFs) was tested in SH-SY5Y cells and human astmcytes. Immunostaining analysis revealed that both cell types accumulated alpha SYN PFFs intracellularly but KYP-2047 decreased intracellular alpha SYN deposits only in SH-SY5Y cells, as astrocytes did not show any PREP activity. Western blot analysis confirmed the reduction of high molecular weight alpha SYN species in SH-SY5Y cell lysates, and secretion of aSYN from SH-SY5Y cells also decreased in the presence of KYP-2407. Accumulation of alpha SYN inside the SH-SY5Y cells resulted in an increase of the auto-lysosomal proteins p62 and LC3BII, as well as calpain 1 and 2, which have been shown to be associated with PD pathology. Notably, treatment with KYP-2407 significantly reduced p62 and LC3BII levels, indicating an increased autophagic flux, and calpain 1 and 2 levels returned to normal in the presence of KYP-2407. Our findings indicate that PREP inhibition can potentially be used as therapy to reduce the insoluble intracellular alpha SYN aggregates.
