Prolyl endopeptidase–alpha-synuclein protein–protein interaction (PREP–αSyn PPI)

The prolyl endopeptidase (PREP)–alpha-synuclein (αSyn) protein–protein interaction is a pathological mechanism where the enzyme PREP acts as a scaffold or chaperone to accelerate the dimerization and aggregation of αSyn (Myöhänen et al., 2012, PubMed: 22733370). αSyn is an intrinsically disordered protein whose aggregation into Lewy bodies is a hallmark of Parkinson's disease and other synucleinopathies (UniProt: P37840). PREP, also known as prolyl oligopeptidase (POP), directly binds to the C-terminal domain of αSyn, facilitating the formation of toxic oligomers (Savolainen et al., 2014, PubMed: 24853123). Therapeutic strategies targeting this interaction involve small molecule PREP inhibitors, such as KYP-2047, which disrupt the PREP–αSyn complex and promote the autophagic clearance of αSyn aggregates (Dokleja et al., 2014, PubMed: 25159598). This target is significant because it offers a way to reduce αSyn toxicity without necessarily eliminating the protein's physiological role in synaptic vesicle trafficking. Clinical interest focuses on the potential for these inhibitors to serve as disease-modifying treatments for neurodegenerative disorders (Svarcbahs et al., 2019, PubMed: 30639344).

Other names

POP–αSyn interactionProlyl oligopeptidase–alpha-synuclein interactionPREP-mediated alpha-synuclein aggregation

Inhibition of prolyl endopeptidase prevents its physical association with alpha-synuclein, thereby blocking the nucleation and dimerization of alpha-synuclein into toxic oligomeric species and promoting autophagic clearance.