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Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy
Diabetic neuropathy (DNP), afflicting sensory and motor nerve fibers, is a major complication in diabetes. The underlying cellular mechanisms of axon degeneration are poorly understood. IGFBP5, an inhibitory binding protein for insulin-like growth factor 1 (IGF1) is highly up-regulated in nerve biop...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4541707/ https://www.ncbi.nlm.nih.gov/pubmed/26025657 http://dx.doi.org/10.1007/s00401-015-1446-8 |
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author | Simon, Christian M. Rauskolb, Stefanie Gunnersen, Jennifer M. Holtmann, Bettina Drepper, Carsten Dombert, Benjamin Braga, Massimiliano Wiese, Stefan Jablonka, Sibylle Pühringer, Dirk Zielasek, Jürgen Hoeflich, Andreas Silani, Vincenzo Wolf, Eckhard Kneitz, Susanne Sommer, Claudia Toyka, Klaus V. Sendtner, Michael |
author_facet | Simon, Christian M. Rauskolb, Stefanie Gunnersen, Jennifer M. Holtmann, Bettina Drepper, Carsten Dombert, Benjamin Braga, Massimiliano Wiese, Stefan Jablonka, Sibylle Pühringer, Dirk Zielasek, Jürgen Hoeflich, Andreas Silani, Vincenzo Wolf, Eckhard Kneitz, Susanne Sommer, Claudia Toyka, Klaus V. Sendtner, Michael |
author_sort | Simon, Christian M. |
collection | PubMed |
description | Diabetic neuropathy (DNP), afflicting sensory and motor nerve fibers, is a major complication in diabetes. The underlying cellular mechanisms of axon degeneration are poorly understood. IGFBP5, an inhibitory binding protein for insulin-like growth factor 1 (IGF1) is highly up-regulated in nerve biopsies of patients with DNP. We investigated the pathogenic relevance of this finding in transgenic mice overexpressing IGFBP5 in motor axons and sensory nerve fibers. These mice develop motor axonopathy and sensory deficits similar to those seen in DNP. Motor axon degeneration was also observed in mice in which the IGF1 receptor (IGF1R) was conditionally depleted in motoneurons, indicating that reduced activity of IGF1 on IGF1R in motoneurons is responsible for the observed effect. These data provide evidence that elevated expression of IGFBP5 in diabetic nerves reduces the availability of IGF1 for IGF1R on motor axons, thus leading to progressive neurodegeneration. Inhibition of IGFBP5 could thus offer novel treatment strategies for DNP. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00401-015-1446-8) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4541707 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-45417072015-08-21 Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy Simon, Christian M. Rauskolb, Stefanie Gunnersen, Jennifer M. Holtmann, Bettina Drepper, Carsten Dombert, Benjamin Braga, Massimiliano Wiese, Stefan Jablonka, Sibylle Pühringer, Dirk Zielasek, Jürgen Hoeflich, Andreas Silani, Vincenzo Wolf, Eckhard Kneitz, Susanne Sommer, Claudia Toyka, Klaus V. Sendtner, Michael Acta Neuropathol Original Paper Diabetic neuropathy (DNP), afflicting sensory and motor nerve fibers, is a major complication in diabetes. The underlying cellular mechanisms of axon degeneration are poorly understood. IGFBP5, an inhibitory binding protein for insulin-like growth factor 1 (IGF1) is highly up-regulated in nerve biopsies of patients with DNP. We investigated the pathogenic relevance of this finding in transgenic mice overexpressing IGFBP5 in motor axons and sensory nerve fibers. These mice develop motor axonopathy and sensory deficits similar to those seen in DNP. Motor axon degeneration was also observed in mice in which the IGF1 receptor (IGF1R) was conditionally depleted in motoneurons, indicating that reduced activity of IGF1 on IGF1R in motoneurons is responsible for the observed effect. These data provide evidence that elevated expression of IGFBP5 in diabetic nerves reduces the availability of IGF1 for IGF1R on motor axons, thus leading to progressive neurodegeneration. Inhibition of IGFBP5 could thus offer novel treatment strategies for DNP. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00401-015-1446-8) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2015-05-30 2015 /pmc/articles/PMC4541707/ /pubmed/26025657 http://dx.doi.org/10.1007/s00401-015-1446-8 Text en © The Author(s) 2015 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. |
spellingShingle | Original Paper Simon, Christian M. Rauskolb, Stefanie Gunnersen, Jennifer M. Holtmann, Bettina Drepper, Carsten Dombert, Benjamin Braga, Massimiliano Wiese, Stefan Jablonka, Sibylle Pühringer, Dirk Zielasek, Jürgen Hoeflich, Andreas Silani, Vincenzo Wolf, Eckhard Kneitz, Susanne Sommer, Claudia Toyka, Klaus V. Sendtner, Michael Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy |
title | Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy |
title_full | Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy |
title_fullStr | Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy |
title_full_unstemmed | Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy |
title_short | Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy |
title_sort | dysregulated igfbp5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy |
topic | Original Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4541707/ https://www.ncbi.nlm.nih.gov/pubmed/26025657 http://dx.doi.org/10.1007/s00401-015-1446-8 |
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