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Proteolytic degradation of neuropeptide Y (NPY) from head to toe: Identification of novel NPY-cleaving peptidases and potential drug interactions in CNS and Periphery

Wagner L1,2,3, Wolf R2, Zeitschel U4, Rossner S4, Petersén Å5, Leavitt BR6, Kästner F7, Rothermundt M7,8, Gärtner UT2, Gündel D9, Schlenzig D3, Frerker N10, Schade J10, Manhart S2, Rahfeld JU1,3, Demuth HU3 and von Hörsten S10.

1Deutschsprachige Selbsthilfegruppe für Alkaptonurie (DSAKU) e.V., Stuttgart, Germany.
2Probiodrug AG, Halle, Germany.
3Fraunhofer-Institute for cell therapy and immunology, Department of Drug Design and Target Validation, Halle, Germany.
4Paul-Flechsig-Institute for Brain Research, University of Leipzig, Leipzig, Germany.
5Translational Neuroendocrine Research Unit, Lund University, Lund, Sweden.
6Department of Medical Genetics, Centre for Molecular Medicine & Therapeutics, University of British Columbia and Children's and Women's Hospital, Vancouver, BC, Canada.
7Department of Psychiatry, University of Muenster, Muenster, Germany.
8St. Rochus-Hospital Telgte, Telgte, Germany.
9Julius Bernstein Institute for Physiology, Martin Luther University of Halle-Wittenberg, Halle, Germany.
10Department of Experimental Therapy, Preclinical Experimental Center, Universitätsklinikum Erlangen, 91054, Erlangen, Germany.

J Neurochem. 135(5): 1019-37 (2015)


The bioactivity of neuropeptide Y (NPY) is either N-terminally modulated with respect to receptor-selectivity by dipeptidyl-peptidase 4 (DP4)-like enzymes or proteolytic degraded by neprilysin or meprins, thereby abrogating signal transduction. However, neither the subcellular nor the compartmental differentiation of these regulatory mechanisms is fully understood. Using mass spectrometry, selective inhibitors and histochemistry, studies across various cell types, body fluids and tissues revealed that most frequently DP4-like enzymes, aminopeptidases P (AmpP), secreted meprin-A (Mep-A) and cathepsin D (CTSD) rapidly hydrolyze NPY, depending on the cell type and tissue under study. Novel degradation of NPY by cathepsins B, D, L, G, S and tissue kallikrein could also be identified. Expression of DP4, CTSD, and Mep-A at the median eminence indicates that the bioactivity of NPY is regulated by peptidases at the interphase between the periphery and the CNS. Detailed ex vivo studies on human sera and CSF samples recognized CTSD as the major NPY-cleaving enzyme in the CSF, whereas an additional C-terminal truncation by angiotensin-converting enzyme (ACE) could be detected in serum. The latter finding hints to potential drug interaction between antidiabetic DP4 inhibitors and anti-hypertensive ACE inhibitors, while it ablates suspected hypertensive side-effects of only antidiabetic DP4-inhibitors application. This article is protected by copyright. All rights reserved.