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Prolyl oligopeptidase and dipeptidyl peptidase II/dipeptidyl peptidase IV ratio in the cerebrospinal fluid in Parkinson’s disease: historical overview and future prospects

  • Translational Neurosciences - Review Article
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Abstract

Prolyl oligopeptidase (also named prolyl endopeptidase; PREP) hydrolyzes the Pro-Xaa bonds of biologically active oligopeptides on their carboxyl side. In 1987, we detected PREP activity in human cerebrospinal fluid (CSF) using highly sensitive liquid chromatography–fluorometry with succinyl-Gly-Pro-4-methyl-coumarin amide as a new synthetic substrate, and found a marked decrease in its activity in the cerebrospinal fluid (CSF) from patients with Parkinson’s disease (PD) as compared with its level in control patients without neurological diseases. In 2013, Hannula et al. found co-localization of PREP with α-synuclein in the postmortem PD brain. Several recent studies also suggest that the level of PREP in the brain of PD patients may be related to dopamine (DA) cell death via promotion of α-synuclein oligomerization and that inhibitors of PREP may play a neuroprotective role in PD. Although the relationship between another family of prolyl oligopeptidase enzymes, dipeptidyl peptidase II (DPP II) and dipeptidyl peptidase IV (DPP IV), and α-synuclein in the PD brain is not yet clear, we found that the DPP II activity/DPP IV activity ratio in the CSF was significantly increased in PD patients. This review discusses the possibility of PREP as well as the DPP II/DPP IV ratio in the CSF as potential biomarkers of PD.

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Acknowledgments

We would like to thank Prof. Kurt Jellinger for providing samples from his brain bank during our collaboration on the biochemistry of the post mortem brain in Parkinson’s disease with Prof. Peter Riederer. Prof. Jellinger has made great contributions to the pathophysiology of neurodegenerative diseases, such as Parkinson’s and Alzheimer’s diseases, mainly by the histochemical approach with over 800 publications. One significant achievement in our collaboration with Prof. Peter Riederer and Prof. Kurt Jellinger on the biochemical analysis of dopamine-synthesizing enzymes in postmortem brain samples from parkinsonian patients was the finding that the homo-specific activity (activity per enzyme protein) of tyrosine hydroxylase, the regulatory enzyme of dopamine synthesis, is increased specifically in the substantia nigra (Mogi et al. 1988b). This work led us to another new study on phosphorylation, stability, and degradation of tyrosine hydroxylase in the brain (Nakashima et al. 2013). We dedicate this review to Prof. Kurt Jellinger on the occasion of his 85th birthday.

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  1. Department of Pharmacology, School of Medicine, Fujita Health University, Toyoake, Aichi, 470-1192, Japan

    Toshiharu Nagatsu

  2. Department of Brain Functions, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, 464-8601, Japan

    Toshiharu Nagatsu

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  1. Toshiharu Nagatsu
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Correspondence to Toshiharu Nagatsu.

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Special Issue on the occasion of the 85th birthday of Prof. Kurt A. Jellinger.

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Nagatsu, T. Prolyl oligopeptidase and dipeptidyl peptidase II/dipeptidyl peptidase IV ratio in the cerebrospinal fluid in Parkinson’s disease: historical overview and future prospects. J Neural Transm 124, 739–744 (2017). https://doi.org/10.1007/s00702-016-1604-8

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  • DOI: https://doi.org/10.1007/s00702-016-1604-8

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