Prolyl oligopeptidase stimulates the aggregation of α-synuclein

Brandt, Inger; Gérard, Melanie; Sergeant, Kjell; Devreese, Bart; Baekelandt, Veerle; Augustyns, Koen; Scharpé, Simon; Engelborghs, Yves; Lambeir, Anne‐Marie

doi:10.1016/j.peptides.2008.05.005

Cited by 80 publications

(92 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…It was previously shown that PREP accelerates aSyn aggregation and that a PREP inhibitor blocks this in vitro and promotes clearance of aSyn aggregates in aSyn-overexpressing cells and in vivo models (14,22). However, although PREP increased the aggregation of aSyn in a cell-free model, the interaction between PREP and aSyn has not been documented earlier.…”

Section: Discussionmentioning

confidence: 96%

“…Although the effect of PREP on aSyn aggregation in a cell-free system (14) indirectly supports this hypothesis, a direct interaction between aSyn and PREP has not been demonstrated. Here, we have used a combination of live-cell and cell-free methods to show that both wild-type PREP and a catalytically inactive mutant PREP with a serine-alanine mutation at residue 554 (S554A) interact with aSyn with low micromolar affinity.…”

mentioning

confidence: 94%

“…One mediator that enhances aSyn aggregation is prolyl oligopeptidase (PREP, POP, EC 3.4.21.26) (14). PREP is an 80-kDa protein with serine protease activity that is widely distributed among the species and can be found in the brain and various other tissues (15).…”

mentioning

confidence: 99%

“…The size of aSyn protein is 140 amino acids, which makes it too large to be hydrolyzed by PREP, and it has been proposed that PREP might serve as a nucleation point for aSyn aggregation (14,20). In addition, PREP colocalizes with aSyn in the substantia nigra in human PD brains (21).…”

mentioning

confidence: 99%

“…In addition, PREP colocalizes with aSyn in the substantia nigra in human PD brains (21). PREP inhibition effectively prevents aSyn aggregation in a cell-free system, in aSyn-overexpressing cells, and in transgenic mouse models (14,22). Recently, we have identified PREP as a negative modulator of autophagosome formation, and treatment with PREP inhibitor, KYP-2047, induced macroautophagy and autophagosome formation via a beclin 1-dependent pathway (23).…”

mentioning

confidence: 99%

See 4 more Smart Citations

Prolyl Oligopeptidase Enhances α-Synuclein Dimerization via Direct Protein-Protein Interaction

Savolainen

Myöhänen

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Prolyl oligopeptidase (PREP) modulates accumulation of aggregated ␣-synuclein both in vitro and in vivo, but the mechanism remains unknown. Results: Using live-cell and cell-free methods, we show that PREP interacts directly with ␣-synuclein. Conclusion: PREP binds to ␣-synuclein and enhances its dimerization. Significance: These results establish a mechanism of how PREP inhibition reduces ␣-synuclein aggregation and support PREP inhibition as a novel therapy in synucleinopathies.

show abstract

Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 94%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Prolyl Oligopeptidase Enhances α-Synuclein Dimerization via Direct Protein-Protein Interaction

Savolainen

Myöhänen

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

Active‐Site‐Directed Inhibitors of Prolyl Oligopeptidase Abolish Its Conformational Dynamics

et al. 2016

View full text Add to dashboard Cite

Deciphering conformational dynamics is crucial for understanding the biological functions of proteins and for designing compounds targeting them. In particular, providing an accurate description of µs-ms motions opens up the opportunity for regulating protein-protein interactions (PPIs) by modulating dynamics of one interacting partner. Here we analyzed the conformational dynamics of prolyl oligopeptidase (POP) and the effects of active site-directed inhibitors on the dynamics. For this purpose, we used an integrated structural biology approach based on NMR spectroscopy and SAXS experiments complemented by MD simulations. Our results found that POP is in a slow equilibrium in solution between open and closed conformations, and that inhibitors effectively prevented this equilibrium by stabilizing the enzyme in a closed conformation.

show abstract

Spatiotemporal expression and inhibition of prolyl oligopeptidase contradict its involvement in key pathologic mechanisms of kainic acid–induced temporal lobe epilepsy in rats

et al. 2018

View full text Add to dashboard Cite

Summary Objective Prolyl oligopeptidase (PREP) has been implicated in neuroinflammatory processes and neuroplasticity and has been suggested as a target for the treatment of neurodegenerative disease. The aim of this investigation was to explore the involvement of PREP in the neuropathologic mechanisms relevant to temporal lobe epilepsy (TLE) using a PREP inhibitor in a well‐established rat model. Methods PREP activity and expression was studied in Sprague‐Dawley rats 2 and 12 weeks following kainic acid–induced status epilepticus (KASE). Continuous video‐electroencephalography monitoring was performed for 2 weeks in the 12‐week cohort to identify a relationship of PREP expression/activity with epileptic seizures. In addition, the animals included in the 2‐week time point were treated with a specific inhibitor of PREP, KYP‐2047, or saline continuously, starting immediately after SE. PREP activity and its expression were analyzed in rat brain by using enzyme kinetics and western blot. In addition, markers for microglial activation, astrogliosis, cell loss, and cell proliferation were evaluated. Results Enzymatic activity of PREP was unchanged following induction of SE after 2 and 12 weeks in rats. PREP activity in epileptic rats did not relate to the number of seizures/day at the 12‐week time point. Moreover, continuous inhibition of PREP for 2 weeks after KASE did not alter the SE‐mediated neuroinflammatory response, cell loss, or cell proliferation in the hippocampal subgranule zone measured at the 2‐week time point. Significance PREP inhibition does not affect key pathologic mechanisms, including activation of glial cells, cell loss, and neural progenitor cell proliferation, in this KASE model of TLE. The results do not support a direct role of PREP in seizure burden during the chronic epilepsy period in this model.

show abstract

Prolyl oligopeptidase stimulates the aggregation of α-synuclein

Cited by 80 publications

References 49 publications

Prolyl Oligopeptidase Enhances α-Synuclein Dimerization via Direct Protein-Protein Interaction

Prolyl Oligopeptidase Enhances α-Synuclein Dimerization via Direct Protein-Protein Interaction

Active‐Site‐Directed Inhibitors of Prolyl Oligopeptidase Abolish Its Conformational Dynamics

Spatiotemporal expression and inhibition of prolyl oligopeptidase contradict its involvement in key pathologic mechanisms of kainic acid–induced temporal lobe epilepsy in rats

Contact Info

Product

Resources

About