ArticleThe Journal of biological chemistry2015
Prolyl oligopeptidase enhances α-synuclein dimerization via direct protein-protein interaction.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 68 citations in OpenAlex.
- Postnatal Mouse Brain Region-Resolved Peptidomic Resource of Conditional Ndel1 Loss: Comparison of Acidic and Alcoholic Extraction Strategies.Journal of neurochemistry · 2025Article
- Recent Advances in Autophagy and Immunotherapy for the Clearance of Aggregated α-Synuclein in Parkinson's Disease.Aging and disease · 2025Review
- Missense variants in CMS22 patients reveal that PREPL has both enzymatic and nonenzymatic functions.JCI insight · 2024Article
- 5-Aminothiazoles Reveal a New Ligand-Binding Site on Prolyl Oligopeptidase Which is Important for Modulation of Its Protein-Protein Interaction-Derived Functions.Journal of medicinal chemistry · 2024Article
- UBL3 Interacts with Alpha-Synuclein in Cells and the Interaction Is Downregulated by the EGFR Pathway Inhibitor Osimertinib.Biomedicines · 2023Article
- Nonpeptidic Oxazole-Based Prolyl Oligopeptidase Ligands with Disease-Modifying Effects on α-Synuclein Mouse Models of Parkinson's Disease.Journal of medicinal chemistry · 2023Article
- Genetic modifiers of synucleinopathies-lessons from experimental models.Oxford open neuroscience · 2023Review
- Dithymoquinone Analogues as Potential Candidate(s) for Neurological Manifestation Associated with COVID-19: A Therapeutic Strategy for Neuro-COVID.Life (Basel, Switzerland) · 2022Article
- Oleuropein as a Potent Compound against Neurological Complications Linked with COVID-19: A Computational Biology Approach.Entropy (Basel, Switzerland) · 2022Article
- Post-Proline Cleaving Enzymes (PPCEs): Classification, Structure, Molecular Properties, and Applications.Plants (Basel, Switzerland) · 2022Review
- Prolyl endopeptidase-like is a (thio)esterase involved in mitochondrial respiratory chain function.iScience · 2021Article
- 2-Imidazole as a Substitute for the Electrophilic Group Gives Highly Potent Prolyl Oligopeptidase Inhibitors.ACS medicinal chemistry letters · 2021Article
- Targeting autophagy using small-molecule compounds to improve potential therapy of Parkinson's disease.Acta pharmaceutica Sinica. B · 2021Review
- Molecular insights into α-synuclein interaction with individual human core histones, linker histone, and dsDNA.Protein science : a publication of the Protein Society · 2021Article
- Prolyl oligopeptidase inhibition reduces alpha-synuclein aggregation in a cellular model of multiple system atrophy.Journal of cellular and molecular medicine · 2021Article
- Cerebral dopamine neurotrophic factor reduces α-synuclein aggregation and propagation and alleviates behavioral alterations in vivo.Molecular therapy : the journal of the American Society of Gene Therapy · 2021Article
- GSAP regulates lipid homeostasis and mitochondrial function associated with Alzheimer's disease.The Journal of experimental medicine · 2021Article
- Monitoring alpha-synuclein oligomerization and aggregation using bimolecular fluorescence complementation assays: What you see is not always what you get.Journal of neurochemistry · 2021Article
- Prolyl Oligopeptidase Regulates Dopamine Transporter Oligomerization and Phosphorylation in a PKC- and ERK-Independent Manner.International journal of molecular sciences · 2021Article
- Therapeutic Effect of Novel Cyanopyrrolidine-Based Prolyl Oligopeptidase Inhibitors in Rat Models of Amnesia.Frontiers in chemistry · 2021Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Prolyl oligopeptidase (PREP) accelerates the aggregation of α-synuclein (aSyn), a key protein involved in development of Parkinson disease and other synucleinopathies. PREP inhibitors reduce aSyn aggregation, but the mechanism has remained unknown. We have now used protein-fragment complementation assays (PCA) and microscale thermophoresis in parallel to show that PREP interacts directly with aSyn in both intact cells and in a cell-free system. Using split luciferase-based PCA, we first showed that PREP enhances the formation of soluble aSyn dimers in live Neuro-2A neuroblastoma cells. A PREP inhibitor, KYP-2047, reduced aSyn dimerization in PREP-expressing cells but not in cells lacking PREP expression. aSyn dimerization was also enhanced by PREP(S554A), an enzymatically inactive PREP mutant, but this was not affected by KYP-2047. PCA and microscale thermophoresis studies showed that aSyn interacts with both PREP and PREP(S554A) with low micromolar affinity. Neither the proline-rich, C-terminal domain of aSyn nor the hydrolytic activity of PREP was required for the interaction with PREP. Our results show that PREP binds directly to aSyn to enhance its dimerization and may thus serve as a nucleation point for aSyn aggregation. Native gel analysis showed that KYP-2047 shifts PREP to a compact monomeric form with reduced ability to promote aSyn nucleation. As PREP inhibition also enhances autophagic clearance of aSyn, PREP inhibitors may reduce accumulation of aSyn inclusions via a dual mechanism and are thus a novel therapeutic candidate for synucleinopathies. Our results also suggest that PREP has other cellular functions in addition to its peptidase activity.
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