Researchers of the Laboratory of Medical Biochemistry significantly contributed to the earlier research on prolyl oligopeptidase (PREP). They cloned the gene and developed assay methods to measure PREP activity in clinical samples. When the crystal structure of PREP was solved, it gave its name to an entirely new family of proteases that also comprises dipeptidyl peptidases 4, 8 and 9.
Prolyl oligopeptidase (PREP) is an endopeptidase that catalyzes the hydrolysis of a peptide bond following proline in short peptides. Since PREP activity in the brain is high and several neuropeptides are cleaved by it, a physiological role in neuropeptide processing and turnover is widely predicted.
Several PREP inhibitors developed during the 1990s were found to have a positive effect on memory, learning and cognition in animal models of Alzheimer’s disease and brain injury. However, not all results of these experiments have been equivocal and so far, no clear picture has emerged that defines the enzyme’s position in the known pathways of peptide processing and degradation.
Currently, functional PREP research no longer exclusively focuses on the enzyme’s peptidase activity, but also addresses potential intracellular actions that affect signal transduction, protein secretion, aging, neuronal development and differentiation.
Several of these studies indicate that protein-protein interactions underlie the role of PREP in the central nervous system. One of the proteins found to interact with PREP is α-synuclein. Our results indicate that PREP promotes aggregation of α-synuclein in vitro
and prolyl oligopeptidase inhibitors reduce α-synuclein protein levels and aggregates in cellular and animal models of Parkinson’s disease.
This observation that active site inhibitors of PREP can also affect protein-protein interactions remains enigmatic and is a topic that calls for the mechanistic reinvestigation of in vivo
effects reported earlier.
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