The effect of prolyl oligopeptidase inhibitors on alpha-synuclein aggregation and autophagy cannot be predicted by their inhibitory efficacy

Kilpeläinen, Tommi; Hellinen, Laura; Vrijdag, Johannes; Xu, Yan; Svarcbahs, Reinis; Vellonen, Kati‐Sisko; Lambeir, Anne‐Marie; Huttunen, Henri J.; Urtti, Arto; Wallén, Erik A.A.; Myöhänen, Timo T.

doi:10.1016/j.biopha.2020.110253

Cited by 21 publications

(57 citation statements)

References 45 publications

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“…In our previous studies, we have shown that a serine protease, prolyl oligopeptidase (PREP), increases aSyn oligomerization via direct protein‐protein interaction 15 , 16 and negatively regulates autophagy. 17 Importantly, small‐molecular PREP inhibitors can interfere with this interaction, leading to decreased aSyn aggregation, 15 , 18 , 19 and PREP inhibition or deletion also stimulates autophagy and increases the degradation of aSyn oligomers 16 , 17 , 18 and fibrils. 20 In aSyn‐based in vivo PD model, PREP inhibition has shown disease‐modifying impact by restoring an aSyn virus vector‐induced behavioural deficit.…”

Section: Introductionmentioning

confidence: 99%

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

Cui

Kilpeläinen

Zouzoula

et al. 2021

J Cellular Molecular Medi

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Section: Introductionmentioning

confidence: 99%

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

Cui

Kilpeläinen

Zouzoula

et al. 2021

J Cellular Molecular Medi

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“…This dual effect is the most attractive characteristic of the interaction of αSyn with POP. Additionally, POP inhibitors were shown to decrease α-Syn dimerization and increase autophagy in cells [ 26 , 31 , 32 ]. Autophagy is the most important cellular pathway to the degradation of aggregated proteins, and the mechanisms via which POP inhibitors induce this cellular response were studied [ 32 , 33 , 34 ].…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, POP inhibitors were shown to decrease α-Syn dimerization and increase autophagy in cells [ 26 , 31 , 32 ]. Autophagy is the most important cellular pathway to the degradation of aggregated proteins, and the mechanisms via which POP inhibitors induce this cellular response were studied [ 32 , 33 , 34 ]. Hence, considering all these in vitro and in vivo studies, POP inhibitors gained attention as potential drugs to treat synucleinopathies (e.g., Parkinson´s disease, PD) [ 26 , 31 , 35 , 36 , 37 , 38 , 39 ].…”

Section: Introductionmentioning

confidence: 99%

Prolyl Endopeptidase-Like Facilitates the α-Synuclein Aggregation Seeding, and This Effect Is Reverted by Serine Peptidase Inhibitor PMSF

et al. 2020

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The aggregation of α-synuclein (α-Syn) is a characteristic of Parkinson’s disease (PD). α-Syn oligomerization/aggregation is accelerated by the serine peptidase, prolyl oligopeptidase (POP). Factors that affect POP conformation, including most of its inhibitors and an impairing mutation in its active site, influence the acceleration of α-Syn aggregation resulting from the interaction of these proteins. It is noteworthy, however, that α-Syn is not cleaved by POP. Prolyl endopeptidase-like (PREPL) protein is structurally related to the serine peptidases belonging to the POP family. Based on the α-Syn–POP studies and knowing that PREPL may contribute to the regulation of synaptic vesicle exocytosis, when this protein can encounter α-Syn, we investigated the α-Syn–PREPL interaction. The binding of these two human proteins was observed with an apparent affinity constant of about 5.7 μM and, as in the α-Syn assays with POP, the presence of PREPL accelerated the oligomerization/aggregation events, with no α-Syn cleavage. Furthermore, despite this lack of hydrolytic cleavage, the serine peptidase active site inhibitor phenylmethylsulfonyl fluoride (PMSF) abolished the enhancement of the α-Syn aggregation by PREPL. Therefore, given the attention to POP inhibitors as potential drugs to treat synucleinopathies, the present data point to PREPL as another potential target to be explored for this purpose.

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“…Small-molecular PREP inhibitors have been shown to reduce αSyn aggregation and increase the clearance of αSyn aggregates via enhanced autophagy in several in vitro and in vivo models. 11 , 13 − 15 Thus, modulation of PREP with small-molecular ligands might be a potential therapeutic strategy to tackle several routes leading to neurodegenerative diseases related to abnormal protein processing such as Parkinson’s disease and Alzheimer’s disease. We have also demonstrated that the effects of PREP ligands on αSyn dimerization and autophagy have no direct correlation to their IC 50 values.…”

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confidence: 99%

“…We have also demonstrated that the effects of PREP ligands on αSyn dimerization and autophagy have no direct correlation to their IC 50 values. 15 , 16 Inhibition of the proteolytic activity has been thoroughly studied, but we are still learning how protein–protein interactions of PREP are regulated. PREP is a highly dynamic protein, where inhibitor binding restricts its conformational freedom, 17 and our working hypothesis is that the functions of PREP are dependent on what conformations PREP can adopt.…”

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confidence: 99%

2-Imidazole as a Substitute for the Electrophilic Group Gives Highly Potent Prolyl Oligopeptidase Inhibitors

Pätsi

Kilpeläinen

Auno

et al. 2021

ACS Med. Chem. Lett.

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Different five-membered nitrogen-containing heteroaromatics in the position of the typical electrophilic group in prolyl oligopeptidase (PREP) inhibitors were investigated and compared to tetrazole. The 2-imidazoles were highly potent inhibitors of the proteolytic activity. The binding mode for the basic imidazole was studied by molecular docking as it was expected to differ from the acidic tetrazole. A new putative noncovalent binding mode with an interaction to His680 was found for the 2-imidazoles. Inhibition of the proteolytic activity did not correlate with the modulating effect on protein–protein-interaction-derived functions of PREP (i.e., dimerization of alpha-synuclein and autophagy). Among the highly potent PREP inhibiting 2-imidazoles, only one was also a potent modulator of PREP-catalyzed alpha-synuclein dimerization, indicating that the linker length on the opposite side of the molecule from the five-membered heteroaromatic is critical for the disconnected structure–activity relationships.

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The effect of prolyl oligopeptidase inhibitors on alpha-synuclein aggregation and autophagy cannot be predicted by their inhibitory efficacy

Cited by 21 publications

References 45 publications

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

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

Prolyl Endopeptidase-Like Facilitates the α-Synuclein Aggregation Seeding, and This Effect Is Reverted by Serine Peptidase Inhibitor PMSF

2-Imidazole as a Substitute for the Electrophilic Group Gives Highly Potent Prolyl Oligopeptidase Inhibitors

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