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

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 - Acta Neuropathol. (2015)

Bottom Line: IGFBP5, an inhibitory binding protein for insulin-like growth factor 1 (IGF1) is highly up-regulated in nerve biopsies of patients with DNP.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.

View Article: PubMed Central - PubMed

Affiliation: Institute for Clinical Neurobiology, University of Würzburg, Versbacher-Str. 5, 97078, Würzburg, Germany.

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.

No MeSH data available.


Related in: MedlinePlus

IGFBP5 decreases the survival promoting downstream effect of IGF1 on isolated wild-type motoneurons. a IGFBP5 (BP5) reduced IGF1-mediated survival effects from 43 to 20 % on wild-type motoneurons after 7 days in culture, while IGFBP5 did not inhibit BDNF-mediated survival. b Downstream activation of IGF1 signaling pathway in wild-type motoneurons after stimulation with different IGF1 concentrations. Wild-type motoneuron cell cultures were grown for 5 days with 5 ng/ml BDNF, starved overnight and pulsed for 20 min with indicated IGF1 concentrations. Western blot analyses revealed the strongest phosphorylation of IGF1R (b, c) and AKT (b, d) with 20 ng/ml IGF1. e Downstream activation of IGF1 signaling pathway in wild-type DRGs after stimulation with IGF1. Wild-type DRG cell cultures were grown for 20 h with 10 ng/ml NGF, starved for 4 h and pulsed for 20 min with indicated factors. Western blot analyses revealed the strongest phosphorylation of IGF1R (e, f) and AKT (e, g) with 20 ng/ml IGF1
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Fig2: IGFBP5 decreases the survival promoting downstream effect of IGF1 on isolated wild-type motoneurons. a IGFBP5 (BP5) reduced IGF1-mediated survival effects from 43 to 20 % on wild-type motoneurons after 7 days in culture, while IGFBP5 did not inhibit BDNF-mediated survival. b Downstream activation of IGF1 signaling pathway in wild-type motoneurons after stimulation with different IGF1 concentrations. Wild-type motoneuron cell cultures were grown for 5 days with 5 ng/ml BDNF, starved overnight and pulsed for 20 min with indicated IGF1 concentrations. Western blot analyses revealed the strongest phosphorylation of IGF1R (b, c) and AKT (b, d) with 20 ng/ml IGF1. e Downstream activation of IGF1 signaling pathway in wild-type DRGs after stimulation with IGF1. Wild-type DRG cell cultures were grown for 20 h with 10 ng/ml NGF, starved for 4 h and pulsed for 20 min with indicated factors. Western blot analyses revealed the strongest phosphorylation of IGF1R (e, f) and AKT (e, g) with 20 ng/ml IGF1

Mentions: Based on the significant up-regulation of IGFBP5 expression in nerves of diabetic patients, we investigated whether IGFBP5 interferes with the effects of IGF1 on cultured spinal motoneurons, grown for 7 days with IGF1 or BDNF (5 ng/ml) alone, or in combination with IGFBP5 (80 ng/ml). IGF1 and BDNF had potent effects on motoneuron survival (P < 0.001, one-way ANOVA). IGF1 maintained 43 % of initially plated motoneurons; BDNF maintained 50 % (Fig. 2a). Addition of IGFBP5 (80 ng/ml) reduced IGF1-mediated survival rates to 20 % (P < 0.001, one-way ANOVA), whereas BDNF-mediated survival rates remained unaffected (P > 0.05, one-way ANOVA) (Fig. 2a). We then tested the phosphorylation of the IGF1R and downstream AKT with increasing IGF1 concentrations (Fig. 2b). We found maximal activation of the receptor and phosphorylation of downstream AKT with 20 ng/ml IGF1 (P < 0.001, one-way ANOVA) (Fig. 2b–d). Addition of IGFBP5 (200 ng/ml) led to significant reduction of IGF1R (P < 0.05, one-way ANOVA), and downstream AKT phosphorylation (P < 0.01, one-way ANOVA), indicating that IGFBP5 is inhibitory for IGF1R activation and survival in cultures of isolated motoneurons (Fig. 2b–d). Similar observations were made with sensory neurons from embryonic lumbar DRGs (Fig. 2e–g). IGFBP5 reduced IGF-mediated activation of the IGF1R (P < 0.05, one-way ANOVA) and AKT (P < 0.05, one-way ANOVA). AKT activation by NGF was not affected.Fig. 2


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

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 - Acta Neuropathol. (2015)

IGFBP5 decreases the survival promoting downstream effect of IGF1 on isolated wild-type motoneurons. a IGFBP5 (BP5) reduced IGF1-mediated survival effects from 43 to 20 % on wild-type motoneurons after 7 days in culture, while IGFBP5 did not inhibit BDNF-mediated survival. b Downstream activation of IGF1 signaling pathway in wild-type motoneurons after stimulation with different IGF1 concentrations. Wild-type motoneuron cell cultures were grown for 5 days with 5 ng/ml BDNF, starved overnight and pulsed for 20 min with indicated IGF1 concentrations. Western blot analyses revealed the strongest phosphorylation of IGF1R (b, c) and AKT (b, d) with 20 ng/ml IGF1. e Downstream activation of IGF1 signaling pathway in wild-type DRGs after stimulation with IGF1. Wild-type DRG cell cultures were grown for 20 h with 10 ng/ml NGF, starved for 4 h and pulsed for 20 min with indicated factors. Western blot analyses revealed the strongest phosphorylation of IGF1R (e, f) and AKT (e, g) with 20 ng/ml IGF1
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Related In: Results  -  Collection

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Fig2: IGFBP5 decreases the survival promoting downstream effect of IGF1 on isolated wild-type motoneurons. a IGFBP5 (BP5) reduced IGF1-mediated survival effects from 43 to 20 % on wild-type motoneurons after 7 days in culture, while IGFBP5 did not inhibit BDNF-mediated survival. b Downstream activation of IGF1 signaling pathway in wild-type motoneurons after stimulation with different IGF1 concentrations. Wild-type motoneuron cell cultures were grown for 5 days with 5 ng/ml BDNF, starved overnight and pulsed for 20 min with indicated IGF1 concentrations. Western blot analyses revealed the strongest phosphorylation of IGF1R (b, c) and AKT (b, d) with 20 ng/ml IGF1. e Downstream activation of IGF1 signaling pathway in wild-type DRGs after stimulation with IGF1. Wild-type DRG cell cultures were grown for 20 h with 10 ng/ml NGF, starved for 4 h and pulsed for 20 min with indicated factors. Western blot analyses revealed the strongest phosphorylation of IGF1R (e, f) and AKT (e, g) with 20 ng/ml IGF1
Mentions: Based on the significant up-regulation of IGFBP5 expression in nerves of diabetic patients, we investigated whether IGFBP5 interferes with the effects of IGF1 on cultured spinal motoneurons, grown for 7 days with IGF1 or BDNF (5 ng/ml) alone, or in combination with IGFBP5 (80 ng/ml). IGF1 and BDNF had potent effects on motoneuron survival (P < 0.001, one-way ANOVA). IGF1 maintained 43 % of initially plated motoneurons; BDNF maintained 50 % (Fig. 2a). Addition of IGFBP5 (80 ng/ml) reduced IGF1-mediated survival rates to 20 % (P < 0.001, one-way ANOVA), whereas BDNF-mediated survival rates remained unaffected (P > 0.05, one-way ANOVA) (Fig. 2a). We then tested the phosphorylation of the IGF1R and downstream AKT with increasing IGF1 concentrations (Fig. 2b). We found maximal activation of the receptor and phosphorylation of downstream AKT with 20 ng/ml IGF1 (P < 0.001, one-way ANOVA) (Fig. 2b–d). Addition of IGFBP5 (200 ng/ml) led to significant reduction of IGF1R (P < 0.05, one-way ANOVA), and downstream AKT phosphorylation (P < 0.01, one-way ANOVA), indicating that IGFBP5 is inhibitory for IGF1R activation and survival in cultures of isolated motoneurons (Fig. 2b–d). Similar observations were made with sensory neurons from embryonic lumbar DRGs (Fig. 2e–g). IGFBP5 reduced IGF-mediated activation of the IGF1R (P < 0.05, one-way ANOVA) and AKT (P < 0.05, one-way ANOVA). AKT activation by NGF was not affected.Fig. 2

Bottom Line: IGFBP5, an inhibitory binding protein for insulin-like growth factor 1 (IGF1) is highly up-regulated in nerve biopsies of patients with DNP.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.

View Article: PubMed Central - PubMed

Affiliation: Institute for Clinical Neurobiology, University of Würzburg, Versbacher-Str. 5, 97078, Würzburg, Germany.

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.

No MeSH data available.


Related in: MedlinePlus