Inhibition of Prolyl Oligopeptidase Restores Spontaneous Motor Behavior in the α-Synuclein Virus Vector–Based Parkinson's Disease Mouse Model by Decreasing α-Synuclein Oligomeric Species in Mouse Brain

Abstract

Decreased clearance of ␣-synuclein (aSyn) and aSyn protein misfolding and aggregation are seen as major factors in the pathogenesis of Parkinson's disease (PD) and other synucleinopathies that leads to disruption in neuronal function and eventually to cell death. Prolyl oligopeptidase (PREP) can accelerate the aSyn aggregation process, while inhibition of PREP by a small molecule inhibitor decreases aSyn oligomer formation and enhances its clearance via autophagy in different aSyn overexpressing cell types and in transgenic PD animal models. In this study, we investigated the impact of chronic PREP inhibition by a small molecule inhibitor, 4-phenylbutanoyl-l-prolyl-2(S)-cyanopyrrolidine (KYP-2047), on aSyn oligomerization, clearance, and underlying spontaneous motor behavior in a virus vectorbased aSyn overexpression mouse model 4 weeks after aSyn microinjections and after the onset of symptomatic forepaw bias. Following 4 weeks of PREP inhibition, we saw an improved spontaneous forelimb use in mice that correlated with a decreased immunoreactivity against oligomer-specific forms of aSyn. Additionally, KYP-2047 had a trend to enhance dopaminergic systems activity. Our results suggest that PREP inhibition exhibits a beneficial effect on the aSyn clearance and aggregation in a virus mediated aSyn overexpression PD mouse model and that PREP inhibitors could be a novel therapeutic strategy for synucleinopathies.

New tricks of prolyl oligopeptidase inhibitors – A common drug therapy for several neurodegenerative diseases

“…It is likely that the aSyn load produced by AAV was high enough to not allow cellular protein clearance machinery to entirely degrade excess aSyn. However, PREP inhibition still had a beneficial effect on mouse motor behavior, which was associated with decrease in soluble higher aSyn oligomer counts in the PREP inhibitor treated animals [75]. Similarly, we had shown that soluble higher aSyn oligomers are reduced in aSyn overexpressing cells after PREP inhibition [73].…”

“…Similarly, we had shown that soluble higher aSyn oligomers are reduced in aSyn overexpressing cells after PREP inhibition [73]. Proteinase K (PK)resistant aSyn inclusions were not decreased as efficiently as soluble forms after PREP inhibition in the mouse AAV aSyn overexpression model [75], and this suggests that it might be related to the inability of the protein degradation pathway to degrade PK-resistant aSyn inclusions after they have been formed.…”

Prolyl oligopeptidase regulates progesterone secretion via the ERK signaling pathway in murine luteal cells

“…In vitro specificity studies revealed that KYP‐2047 was a potent and selective inhibitor of POP, and currently, it is widely used in in vitro and in vivo studies. (Bainbridge et al, ; Myöhänen, Hannula, et al, ; Svarcbahs, Julku, & Myohanen, ). We found that POP overexpression increased progesterone production in primary luteal cells (Figure d).…”

Downregulation of tyrosine hydroxylase phenotype after AAV injection above substantia nigra: Caution in experimental models of Parkinson’s disease

“…Additionally, the time length of the experiment, 8 weeks, could have been a factor in TH loss, since while there was a functional effect, it may have taken longer to observe a more robust loss of TH across all animals. Also, at 8 weeks, enough potentially toxic aggregates may not be present in the brain to cause loss of TH neurons, such as in an AAV mouse study that only started to show Proteinase K‐resistant α‐syn at 8 weeks (Svarcbahs, Julku, & Myohanen, ). However, several AAV‐α‐syn experiments have been conducted for 8 weeks or less and observed TH loss (Gombash et al, ; Gully et al, ), though how many animals showed the loss is less clear.…”