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

Savolainen, Mari; Xu, Yan; Myöhänen, Timo T.; Huttunen, Henri J.

doi:10.1074/jbc.m114.592931

Cited by 62 publications

(95 citation statements)

References 56 publications

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“…Our group has done additional experiments on PREP and aSyn interactions, and we have confirmed PREP-aSyn interaction in vitro. Notably, we have shown that PREP increased aSyn dimerization by direct protein-protein interaction [64]. This effect is independent of PREP activity but only treatment of catalytically active PREP with a PREP inhibitor, KYP-2047, reduced aSyn dimerization while the S554A-PREP-mediated aSyn dimerization process remained unchanged.…”

Section: Prep Interacts With Asyn To Increase Its Aggregationmentioning

confidence: 74%

New tricks of prolyl oligopeptidase inhibitors – A common drug therapy for several neurodegenerative diseases

Svarcbahs

Julku

Kilpeläinen

et al. 2019

Biochemical Pharmacology

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Section: Prep Interacts With Asyn To Increase Its Aggregationmentioning

confidence: 74%

New tricks of prolyl oligopeptidase inhibitors – A common drug therapy for several neurodegenerative diseases

Svarcbahs

Julku

Kilpeläinen

et al. 2019

Biochemical Pharmacology

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“…22,38,42 In addition to its involvement in neuroinflammation, PREP has been suggested to play a role in other neurodegenerative diseases and synaptic plasticity. There is evidence that PREP is involved in molecular interactions, eliciting an effect that is independent of its peptidase activity, but nevertheless may be modulated by inhibitor binding.…”

Section: Discussionmentioning

confidence: 99%

“…There is evidence that PREP is involved in molecular interactions, eliciting an effect that is independent of its peptidase activity, but nevertheless may be modulated by inhibitor binding. 22,38,42 In addition to its involvement in neuroinflammation, PREP has been suggested to play a role in other neurodegenerative diseases and synaptic plasticity. 14,17,23 Furthermore, it has been frequently associated with secretion of neuropeptides and related to cognitive functions in the brain.…”

Section: Discussionmentioning

confidence: 99%

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

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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.

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“…PREP is involved in the synthesis of the anti-fibrotic peptide N-acetyl-serylaspartyl-lysyl-proline (97). It has been shown that PREP interacts with α-synuclein and accelerates its aggregation (98,99). Additional interaction partners are glyceraldehyde-3-phosphate dehydrogenase (100), growth-associated protein 43 (101,102) and tubulin (90).…”

Section: Prepmentioning

confidence: 99%

The expression of proline-specific enzymes in the human lung

Vliegen¹,

Raju²,

Adriaensen³

et al. 2017

Ann. Transl. Med.

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The pathophysiology of lung diseases is very complex and proteolytic enzymes may play a role or could be used as biomarkers. In this review, the literature was searched to make an overview of what is known on the expression of the proline-specific peptidases dipeptidyl peptidase (DPP) 4, 8, 9, prolyl oligopeptidase (PREP) and fibroblast activation protein α (FAP) in the healthy and diseased lung. Search terms included asthma, chronic obstructive pulmonary disease (COPD), lung cancer, fibrosis, ischemia reperfusion injury and pneumonia. Knowledge on the loss or gain of protein expression and activity during disease might tie these enzymes to certain cell types, substrates or interaction partners that are involved in the pathophysiology of the disease, ultimately leading to the elucidation of their functional roles and a potential therapeutic target. Most data could be found on DPP4, while the other enzymes are less explored. Published data however often appear to be conflicting, the applied methods divers and the specificity of the assays used questionable. In conclusion, information on the expression of the proline-specific peptidases in the healthy and diseased lung is lacking, begging for further well-designed research.

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

Cited by 62 publications

References 56 publications

New tricks of prolyl oligopeptidase inhibitors – A common drug therapy for several neurodegenerative diseases

New tricks of prolyl oligopeptidase inhibitors – A common drug therapy for several neurodegenerative diseases

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

The expression of proline-specific enzymes in the human lung

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