Specific Inhibitor for Prolyl Endopeptidase Suppresses the Generation of Amyloid β Protein in NG108-15 Cells

Shinoda, Masahiko; Toide, Katsuo; Ohsawa, Ikuroh; Kohsaka, Shinichi

doi:10.1006/bbrc.1997.6730

Cited by 42 publications

(29 citation statements)

References 25 publications

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“…PEP inhibitors have also been shown to have neuroprotective and memory-enhancing effects that have been attributed to their ability to modify neuropeptide metabolism (Cunningham and O'Connor, 1997;Makinen et al, 1994). PEP may be a key enzyme in the production of Ab by neurons since a specific PEP inhibitor is reported to reduce Ab secretion from the NG108-15 neuronal cell line (Shinoda et al, 1997). Taken together with our findings, these overall results strongly suggest that PEP activity be further investigated in a spectrum of degenerative neurological disorders.…”

supporting

confidence: 79%

Prolyl endopeptidase is revealed following SILAC analysis to be a novel mediator of human microglial and THP‐1 cell neurotoxicity

Klegeris

Bammler

et al. 2008

Glia

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Reactive microglial cells may exacerbate the pathology in some neurodegenerative disorders. Supernatants of stimulated human microglial cells, or their surrogate THP-1 cells, are lethal to cultured human neuroblastoma SH-SY5Y cells. To explore this neurotoxicity, we examined the spectrum of proteins generated by THP-1 cells using the technique of stable isotope labeling by amino acids in cell culture (SILAC). Unstimulated cells were grown in medium with light L-[(12)C(6)] arginine while cells stimulated by lipopolysaccharide (LPS) plus interferon-gamma (IFN-gamma) were grown in medium with heavy L-[(13)C(6)] arginine. Proteins isolated from the media were digested with trypsin, and relative concentrations of generated peptides determined by mass spectrometry. More than 1,500 proteins or putative proteins were identified. Of these, 174 were increased and 189 decreased by more than twofold in the stimulated cell supernatant. We selected one upregulated protein, prolyl endopeptidase (PEP), for further investigation of its potential contribution to neurotoxicity. We first confirmed its upregulation by comparing its enzymatic activity in stimulated and unstimulated cell supernatants. We then evaluated two specific PEP inhibitors, Boc-Asn-Phe-Pro-aldehyde and Z-Pro-Pro-aldehyde-dimethyl acetal, for their potential to reduce toxicity of stimulated THP-1 cell and human microglia supernatants towards SH-SY5Y cells. We found both to be partially protective in a concentration-dependent manner. Inhibition of PEP may be a therapeutic approach to neurodegenerative disorders including Alzheimer and Parkinson diseases.

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supporting

confidence: 79%

Prolyl endopeptidase is revealed following SILAC analysis to be a novel mediator of human microglial and THP‐1 cell neurotoxicity

Klegeris

Bammler

et al. 2008

Glia

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“…These ligands were either downloaded from PubChem or were constructed using CHEMDRAW software. Few other ligands like Y-29794 [46]–[48], UAMC [49], ono-1603 [50]–[51], S-17092 [52]–[56], SUAM-1221 [57]–[61], and JTP4819 [62]–[67] were also considered for this study. Coordinates were saved and subjected to CORINA for two dimensional to three dimensional conversions.…”

Section: Methodsmentioning

confidence: 99%

Structural Analysis of Prolyl Oligopeptidases Using Molecular Docking and Dynamics: Insights into Conformational Changes and Ligand Binding

Kaushik

Sowdhamini

2011

PLoS ONE

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Prolyl oligopeptidase (POP) is considered as an important pharmaceutical target for the treatment of numerous diseases. Despite enormous studies on various aspects of POPs structure and function still some of the questions are intriguing like conformational dynamics of the protein and interplay between ligand entry/egress. Here, we have used molecular modeling and docking based approaches to unravel questions like differences in ligand binding affinities in three POP species (porcine, human and A. thaliana). Despite high sequence and structural similarity, they possess different affinities for the ligands. Interestingly, human POP was found to be more specific, selective and incapable of binding to a few planar ligands which showed extrapolation of porcine POP in human context is more complicated. Possible routes for substrate entry and product egress were also investigated by detailed analyses of molecular dynamics (MD) simulations for the three proteins. Trajectory analysis of bound and unbound forms of three species showed differences in conformational dynamics, especially variations in β-propeller pore size, which was found to be hidden by five lysine residues present on blades one and seven. During simulation, β-propeller pore size was increased by ∼2 Å in porcine ligand-bound form which might act as a passage for smaller product movement as free energy barrier was reduced, while there were no significant changes in human and A. thaliana POPs. We also suggest that these differences in pore size could lead to fundamental differences in mode of product egress among three species. This analysis also showed some functionally important residues which can be used further for in vitro mutagenesis and inhibitor design. This study can help us in better understanding of the etiology of POPs in several neurodegenerative diseases.

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“…These effects of PEP inhibitors have been attributed to the protection of neuropeptides that facilitate cholinergic neurotransmission such as SP and TRH (Toide et al, 1993;Kouznetsova and Nistri, 2000) against degradation by PEP. It has been shown previously that selective PEP inhibitors suppress in vitro ␤-amyloid protein formation (Shinoda et al, 1997) and prevent in vivo amyloid deposition in the hippocampus of senescence-accelerated mice (Kato et al, 1997). Thus, the present data showing that the cerebral cortex and hippocampus are enriched with PEP mRNA support the view that PEP inhibitors may represent a new therapeutic approach for the treatment of Alzheimer's disease (Kato et al, 1997;Toide et al, 1998).…”

Section: Functional Implicationsmentioning

confidence: 97%

Localization of the mRNA encoding prolyl endopeptidase in the rat brain and pituitary

Bellemère

Vaudry

Mounien

et al. 2004

J of Comparative Neurology

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Prolyl endopeptidase (EC 3.4.21.26, PEP), a serine protease that hydrolyzes peptides at the carboxyl side of proline residues, is involved in the breakdown of several proline-containing neuropeptides and, thus, may contribute to the regulation of behavioral activities. In this study, the distribution of PEP mRNA was investigated in the central nervous system and pituitary of rat by means of quantitative reverse transcriptase-polymerase chain reaction analysis and in situ hybridization histochemistry. High densities of PEP transcripts were found in cerebellar Purkinje and granule cells, within most hypothalamic nuclei, in pyramidal neurons of the Ammon's horn, in granule cells of the dentate gyrus, and within the basolateral complex of the amygdala. Moderate levels of PEP mRNA were observed in layers 3-5 of the cerebral cortex, the anterior thalamic group, the septal region, the substantia nigra, the magnocellular neurons of the red nucleus, and the motor nuclei of the cranial nerves. Low concentrations of PEP mRNA were detected in the deep mesencephalic nuclei, the reticular formation, the pretectum, and the tectum. A high density of PEP mRNA was found in the intermediate and the anterior lobes of the pituitary, while the neural lobe was devoid of labeling. In several brain regions, the distribution pattern of PEP mRNA overlapped that of various neuropeptide receptors, suggesting that PEP is actually involved in the inactivation of regulatory neuropeptides.

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Specific Inhibitor for Prolyl Endopeptidase Suppresses the Generation of Amyloid β Protein in NG108-15 Cells

Cited by 42 publications

References 25 publications

Prolyl endopeptidase is revealed following SILAC analysis to be a novel mediator of human microglial and THP‐1 cell neurotoxicity

Prolyl endopeptidase is revealed following SILAC analysis to be a novel mediator of human microglial and THP‐1 cell neurotoxicity

Structural Analysis of Prolyl Oligopeptidases Using Molecular Docking and Dynamics: Insights into Conformational Changes and Ligand Binding

Localization of the mRNA encoding prolyl endopeptidase in the rat brain and pituitary

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