Prolyl Oligopeptidase Mechanisms in Neurological Disorders

Prolyl oligopeptidase (PREP) is a widely expressed serine protease that cleaves short proline-containing peptides and acts as a multifunctional regulator of neuronal homeostasis. Beyond its classical peptidase activity, PREP engages in direct protein–protein interactions that influence key processes such as neuropeptide signalling, proteostasis, autophagy and mitochondrial function. In neurodegenerative conditions, aberrant PREP activity or conformation has been linked to the promotion of pathological protein aggregates, notably α-synuclein oligomers, and to impaired clearance pathways. Emerging evidence supports a dual role for PREP: its catalytic function may modulate neuropeptide turnover, while conformational switching governs interactions with aggregation-prone proteins and autophagic machinery. Dysregulation of PREP has been implicated in synucleinopathies, tauopathies and broader age-related cognitive decline, making it a prime target for mechanistic dissection and therapeutic intervention. Recent advances have elucidated how distinct classes of PREP ligands can stabilise or disrupt its interaction networks, offering routes to attenuate toxic protein assemblies, restore proteostatic flux and ameliorate motor and cognitive deficits in preclinical models.

Research from Nature Portfolio

In a foundational investigation, virtual screening based on a pharmacophore model identified novel small molecules that inhibit PREP and reduce α-synuclein expression in human neuroblastoma cells. Structure-based docking and molecular dynamics revealed key hydrogen-bond and hydrophobic interactions with the PREP active-site pocket, surpassing the binding affinity of reference inhibitors. Treatment with lead compounds led to a concentration-dependent decrease in α-synuclein levels and mitigated neurotoxic stress in cellular models, highlighting their potential as starting points for drug development in synucleinopathies.

Prolyl Oligopeptidase Mechanisms in Neurological Disorders publication trend

The graph below shows the total number of articles in prolyl oligopeptidase mechanisms in neurological disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Prolyl oligopeptidase (PREP): A serine protease that cleaves short proline-containing peptides and also participates in non-enzymatic interactions within cells.

α-Synuclein: A neuronal protein implicated in synaptic function whose misfolding and aggregation are central to synucleinopathies.

Protein–protein interaction (PPI): The specific physical association between two or more proteins that influences cellular pathways.

Autophagy: A cellular process for degrading and recycling cytoplasmic components, including protein aggregates.

References

1. Mechanism of Action of Prolyl Oligopeptidase (PREP) in Degenerative Brain Diseases: Has Peptidase Activity Only a Modulatory Role on the Interactions of PREP with Proteins?. Frontiers in Aging Neuroscience (2017).
2. Prolyl Oligopeptidase Enhances α-Synuclein Dimerization via Direct Protein-Protein Interaction*. Journal of Biological Chemistry (2015).
3. New compounds identified through in silico approaches reduce the α-synuclein expression by inhibiting prolyl oligopeptidase in vitro. Scientific Reports (2017).
4. Nonpeptidic Oxazole-Based Prolyl Oligopeptidase Ligands with Disease-Modifying Effects on α‑Synuclein Mouse Models of Parkinson’s Disease. Journal of Medicinal Chemistry (2023).
5. The effect of prolyl oligopeptidase inhibitors on alpha-synuclein aggregation and autophagy cannot be predicted by their inhibitory efficacy. Biomedicine & Pharmacotherapy (2020).