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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-overexpressing mice show decreased activation of IGF1 receptor that corresponds to motoneuron degeneration and myelination defects. a, b Immunoprecipitation of the IGF1 receptor from spinal cord (left panel) and sciatic nerve (right panel) extracts of 4-day-old mice and subsequent analysis of phosphorylation showed decreased activation levels in Igfbp5 tg+ mice compared to controls. SN supernatant, IP immunoprecipitation. c Localization of Igfbp5 in cross sections of sciatic nerves. Igfbp5 was increased in axons and extracellular matrix of Igfbp5 tg+ mice. Arrows depict extracellular matrix staining. Scale bar 5 µm. d Representative photomicrograph of myelinated fibers in semithin cross sections of the sciatic nerve of 6-month-old wild-type and Igfbp5 tg+ animals. Scale bar 10 µm. e 5- to 6-month-old Igfbp5 tg+ mice showed a 14 % loss of sciatic nerve fibers. f The frequency of fibers with a circumference between 20–25 μm was decreased by 4.5 % in the sciatic nerve of 6-month-old Igfbp5 tg+ mice. g The M-ratio was significantly reduced by 20 % in 6-month-old Igfbp5 tg+ mice
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Fig5: IGFBP5-overexpressing mice show decreased activation of IGF1 receptor that corresponds to motoneuron degeneration and myelination defects. a, b Immunoprecipitation of the IGF1 receptor from spinal cord (left panel) and sciatic nerve (right panel) extracts of 4-day-old mice and subsequent analysis of phosphorylation showed decreased activation levels in Igfbp5 tg+ mice compared to controls. SN supernatant, IP immunoprecipitation. c Localization of Igfbp5 in cross sections of sciatic nerves. Igfbp5 was increased in axons and extracellular matrix of Igfbp5 tg+ mice. Arrows depict extracellular matrix staining. Scale bar 5 µm. d Representative photomicrograph of myelinated fibers in semithin cross sections of the sciatic nerve of 6-month-old wild-type and Igfbp5 tg+ animals. Scale bar 10 µm. e 5- to 6-month-old Igfbp5 tg+ mice showed a 14 % loss of sciatic nerve fibers. f The frequency of fibers with a circumference between 20–25 μm was decreased by 4.5 % in the sciatic nerve of 6-month-old Igfbp5 tg+ mice. g The M-ratio was significantly reduced by 20 % in 6-month-old Igfbp5 tg+ mice

Mentions: To test whether neuronal IGFBP5 overexpression reduces responsiveness to endogenous IGF1, we immunoprecipitated the IGF1R from the spinal cord and sciatic nerve of 4-day-old Igfbp5 transgenic mice, a time period when endogenous IGF1 levels are high. Analyses of spinal cord and sciatic nerve extracts by Western blot with a specific pIGF1R antibody revealed a significant 35 % reduction in the phosphorylation of the IGF1R (P < 0.01, two-tailed Student’s t test) (Fig. 5a, b). Elevated IGFBP5 immunoreactivity was observed in axons of the sciatic nerve and the extracellular matrix of Igfbp5 transgenic mice (see arrows in Fig. 5c), closely resembling the distribution of IGFBP5 in sural nerve biopsies of patients with DNP (Fig. 1d).Fig. 5


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-overexpressing mice show decreased activation of IGF1 receptor that corresponds to motoneuron degeneration and myelination defects. a, b Immunoprecipitation of the IGF1 receptor from spinal cord (left panel) and sciatic nerve (right panel) extracts of 4-day-old mice and subsequent analysis of phosphorylation showed decreased activation levels in Igfbp5 tg+ mice compared to controls. SN supernatant, IP immunoprecipitation. c Localization of Igfbp5 in cross sections of sciatic nerves. Igfbp5 was increased in axons and extracellular matrix of Igfbp5 tg+ mice. Arrows depict extracellular matrix staining. Scale bar 5 µm. d Representative photomicrograph of myelinated fibers in semithin cross sections of the sciatic nerve of 6-month-old wild-type and Igfbp5 tg+ animals. Scale bar 10 µm. e 5- to 6-month-old Igfbp5 tg+ mice showed a 14 % loss of sciatic nerve fibers. f The frequency of fibers with a circumference between 20–25 μm was decreased by 4.5 % in the sciatic nerve of 6-month-old Igfbp5 tg+ mice. g The M-ratio was significantly reduced by 20 % in 6-month-old Igfbp5 tg+ mice
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Related In: Results  -  Collection

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Fig5: IGFBP5-overexpressing mice show decreased activation of IGF1 receptor that corresponds to motoneuron degeneration and myelination defects. a, b Immunoprecipitation of the IGF1 receptor from spinal cord (left panel) and sciatic nerve (right panel) extracts of 4-day-old mice and subsequent analysis of phosphorylation showed decreased activation levels in Igfbp5 tg+ mice compared to controls. SN supernatant, IP immunoprecipitation. c Localization of Igfbp5 in cross sections of sciatic nerves. Igfbp5 was increased in axons and extracellular matrix of Igfbp5 tg+ mice. Arrows depict extracellular matrix staining. Scale bar 5 µm. d Representative photomicrograph of myelinated fibers in semithin cross sections of the sciatic nerve of 6-month-old wild-type and Igfbp5 tg+ animals. Scale bar 10 µm. e 5- to 6-month-old Igfbp5 tg+ mice showed a 14 % loss of sciatic nerve fibers. f The frequency of fibers with a circumference between 20–25 μm was decreased by 4.5 % in the sciatic nerve of 6-month-old Igfbp5 tg+ mice. g The M-ratio was significantly reduced by 20 % in 6-month-old Igfbp5 tg+ mice
Mentions: To test whether neuronal IGFBP5 overexpression reduces responsiveness to endogenous IGF1, we immunoprecipitated the IGF1R from the spinal cord and sciatic nerve of 4-day-old Igfbp5 transgenic mice, a time period when endogenous IGF1 levels are high. Analyses of spinal cord and sciatic nerve extracts by Western blot with a specific pIGF1R antibody revealed a significant 35 % reduction in the phosphorylation of the IGF1R (P < 0.01, two-tailed Student’s t test) (Fig. 5a, b). Elevated IGFBP5 immunoreactivity was observed in axons of the sciatic nerve and the extracellular matrix of Igfbp5 transgenic mice (see arrows in Fig. 5c), closely resembling the distribution of IGFBP5 in sural nerve biopsies of patients with DNP (Fig. 1d).Fig. 5

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