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

Wagner, Leona; Björkqvist, Maria LU ; Hult Lundh, Sofia LU ; Wolf, Raik; Börgel, Arne; Schlenzig, Dagmar; Ludwig, Hans-Henning; Rahfeld, Jens-Ulrich; Leavitt, Blair and Demuth, Hans-Ulrich, et al. (2016) In Journal of Neurochemistry 137(5). p.820-837
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... (More)

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.

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published
subject
keywords
Huntington′s disease
in
Journal of Neurochemistry
volume
137
issue
5
pages
820 - 837
publisher
Wiley-Blackwell
external identifiers
  • Scopus:84969204273
ISSN
1471-4159
DOI
10.1111/jnc.13624
language
English
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yes
id
ed97c0ad-be94-4df9-a7d1-4ef8140e9f62
date added to LUP
2016-04-18 14:31:17
date last changed
2016-11-03 08:29:02
@misc{ed97c0ad-be94-4df9-a7d1-4ef8140e9f62,
  abstract     = {<p>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.</p>},
  author       = {Wagner, Leona and Björkqvist, Maria and Hult Lundh, Sofia and Wolf, Raik and Börgel, Arne and Schlenzig, Dagmar and Ludwig, Hans-Henning and Rahfeld, Jens-Ulrich and Leavitt, Blair and Demuth, Hans-Ulrich and Petersén, Åsa and von Hörsten, Stephan},
  issn         = {1471-4159},
  keyword      = {Huntington′s disease},
  language     = {eng},
  month        = {03},
  number       = {5},
  pages        = {820--837},
  publisher    = {ARRAY(0x979a5d8)},
  series       = {Journal of Neurochemistry},
  title        = {Neuropeptide Y (NPY) in cerebrospinal fluid from patients with Huntington's Disease : increased NPY levels and differential degradation of the NPY1-30 fragment},
  url          = {http://dx.doi.org/10.1111/jnc.13624},
  volume       = {137},
  year         = {2016},
}