Neuropeptide Y (NPY) in cerebrospinal fluid from patients with Huntington's Disease: increased NPY levels and differential degradation of the NPY1-30 fragment

Research output: Contribution to journalArticle

Abstract

Huntington's disease (HD) is an inherited and fatal polyglutamine neurodegenerative disorder caused by an expansion of the CAG triplet repeat coding region within the HD gene. Progressive dysfunction and loss of striatal GABAergic medium spiny neurons (MSNs) may account for some of the characteristic symptoms in HD patients. Interestingly, in HD, MSNs expressing neuropeptide Y (NPY) are spared and their numbers is even up-regulated in HD patients. In line with this, we report here on increased immuno-linked NPY (IL-NPY) levels in human cerebrospinal fluid (hCSF) from HD patients. As this antibody-based detection of NPY may provide false positive differences due to the antibody-based detections of only fragments of NPY, the initial finding was validated by investigating the proteolytic stability of NPY in hCSF using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and selective inhibitors. A comparison between resulting NPY-fragments and detailed epitope analysis verified significant differences of IL-NPY1-36/3-36 and NPY1-30 levels between HD patients and control subjects. Ex vivo degradomics analysis demonstrated that NPY is initially degraded to NPY1-30 by cathepsin D (CTSD) in both HD patients and control subjects. Yet, NPY1-30 is then further differentially hydrolyzed by thimet oligopeptidase (TOP) in HD patients and by neprilysin (NEP) in control subjects. Furthermore, altered hCSF TOP-inhibitor Dynorphin A1-13 (Dyn-A1-13 ) and TOP-substrate Dyn-A1-8 levels indicate an impaired Dyn-A-TOP network in HD patients. Thus, we conclude that elevated IL-NPY-levels in conjunction with TOP- / NEP-activity/protein as well as Dyn-A1-13 -protein levels may serve as a potential biomarker in human CSF of HD. This article is protected by copyright. All rights reserved.

Details

Authors
  • Leona Wagner
  • Maria Björkqvist
  • Sofia Hult Lundh
  • Raik Wolf
  • Arne Börgel
  • Dagmar Schlenzig
  • Hans-Henning Ludwig
  • Jens-Ulrich Rahfeld
  • Blair Leavitt
  • Hans-Ulrich Demuth
  • Åsa Petersén
  • Stephan von Hörsten
Organisations
External organisations
  • Deutschsprachige Selbsthilfegruppe für Alkaptonurie e.V
  • Klinikum St. Georg, Leipzig
  • University of Mainz
  • Probiodrug AG
  • Fraunhofer Institute for Cell Therapy and Immunology
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Neurosciences

Keywords

  • Huntington′s disease
Original languageEnglish
Pages (from-to)820-837
JournalJournal of Neurochemistry
Volume137
Issue number5
Publication statusPublished - 2016 Mar 26
Publication categoryResearch
Peer-reviewedYes