Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy

Christian M. Simon, Stefanie Rauskolb, Jennifer M. Gunnersen, Bettina Holtmann, Carsten Drepper, Benjamin Dombert, Massimiliano Braga, Stefan Wiese, Sibylle Jablonka, Dirk Pühringer, Jürgen Zielasek, Andreas Hoeflich, Vincenzo Silani, Eckhard Wolf, Susanne Kneitz, Claudia Sommer, Klaus V. Toyka, Michael Sendtner

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)373-387
Number of pages15
JournalActa Neuropathologica
Volume130
Issue number3
DOIs
Publication statusPublished - May 30 2015

Fingerprint

Diabetic Neuropathies
Motor Neurons
Axons
Somatomedins
Nerve Fibers
Somatomedin Receptors
Insulin-Like Growth Factor Binding Protein 1
Diabetes Complications
Transgenic Mice
Biopsy
Therapeutics

Keywords

  • Axonal degeneration
  • Diabetic polyneuropathy
  • Motor nerve biopsy
  • Neuropathy
  • Neurotrophic factors

ASJC Scopus subject areas

  • Clinical Neurology
  • Pathology and Forensic Medicine
  • Cellular and Molecular Neuroscience

Cite this

Simon, C. M., Rauskolb, S., Gunnersen, J. M., Holtmann, B., Drepper, C., Dombert, B., ... Sendtner, M. (2015). Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy. Acta Neuropathologica, 130(3), 373-387. https://doi.org/10.1007/s00401-015-1446-8

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.

In: Acta Neuropathologica, Vol. 130, No. 3, 30.05.2015, p. 373-387.

Research output: Contribution to journalArticle

Simon, CM, Rauskolb, S, Gunnersen, JM, Holtmann, B, Drepper, C, Dombert, B, Braga, M, Wiese, S, Jablonka, S, Pühringer, D, Zielasek, J, Hoeflich, A, Silani, V, Wolf, E, Kneitz, S, Sommer, C, Toyka, KV & Sendtner, M 2015, 'Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy', Acta Neuropathologica, vol. 130, no. 3, pp. 373-387. https://doi.org/10.1007/s00401-015-1446-8
Simon CM, Rauskolb S, Gunnersen JM, Holtmann B, Drepper C, Dombert B et al. Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy. Acta Neuropathologica. 2015 May 30;130(3):373-387. https://doi.org/10.1007/s00401-015-1446-8
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. In: Acta Neuropathologica. 2015 ; Vol. 130, No. 3. pp. 373-387.
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