Top

Published in:

Open Access 01-09-2015 | Original Paper

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

Authors: 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

Published in: Acta Neuropathologica | Issue 3/2015

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.

Available only for authorised users

Bach LA, Headey SJ, Norton RS (2005) IGF-binding proteins–the pieces are falling into place. Trends Endocrinol Metab 16:228–234. doi:10.1016/j.tem.2005.05.005 CrossRefPubMed

Beattie J, Allan GJ, Lochrie JD, Flint DJ (2006) Insulin-like growth factor-binding protein-5 (IGFBP-5): a critical member of the IGF axis. Biochem J 395:1–19. doi:10.1042/BJ20060086 CrossRefPubMedCentralPubMed

Beck KD, Powell-Braxton L, Widmer HR, Valverde J, Hefti F (1995) Igf1 gene disruption results in reduced brain size, CNS hypomyelination, and loss of hippocampal granule and striatal parvalbumin-containing neurons. Neuron 14:717–730CrossRefPubMed

Bondy C, Lee WH (1993) Correlation between insulin-like growth factor (IGF)-binding protein 5 and IGF-I gene expression during brain development. J Neurosci 13:5092–5104PubMed

Boulton AJ, Ward JD (1986) Diabetic neuropathies and pain. Clin Endocrinol Metab 15:917–931CrossRefPubMed

Bremer J, Baumann F, Tiberi C, Wessig C, Fischer H, Schwarz P, Steele AD, Toyka KV, Nave KA, Weis J et al (2010) Axonal prion protein is required for peripheral myelin maintenance. Nat Neurosci 13:310–318. doi:10.1038/nn.2483 CrossRefPubMed

Caroni P (1993) Activity-sensitive signaling by muscle-derived insulin-like growth factors in the developing and regenerating neuromuscular system. Ann N Y Acad Sci 692:209–222CrossRefPubMed

Caroni P, Grandes P (1990) Nerve sprouting in innervated adult skeletal muscle induced by exposure to elevated levels of insulin-like growth factors. J Cell Biol 110:1307–1317CrossRefPubMed

Carson MJ, Behringer RR, Brinster RL, McMorris FA (1993) Insulin-like growth factor I increases brain growth and central nervous system myelination in transgenic mice. Neuron 10:729–740CrossRefPubMed

10.

Cheng HL, Randolph A, Yee D, Delafontaine P, Tennekoon G, Feldman EL (1996) Characterization of insulin-like growth factor-I and its receptor and binding proteins in transected nerves and cultured Schwann cells. J Neurochem 66:525–536CrossRefPubMed

11.

Cheng HL, Russell JW, Feldman EL (1999) IGF-I promotes peripheral nervous system myelination. Ann N Y Acad Sci 883:124–130CrossRefPubMed

12.

Cheng HL, Sullivan KA, Feldman EL (1996) Immunohistochemical localization of insulin-like growth factor binding protein-5 in the developing rat nervous system. Brain Res Dev Brain Res 92:211–218CrossRefPubMed

13.

Clemmons DR (1997) Insulin-like growth factor binding proteins and their role in controlling IGF actions. Cytokine Growth Factor Rev 8:45–62CrossRefPubMed

14.

Clemmons DR, Jones JI, Busby WH, Wright G (1993) Role of insulin-like growth factor binding proteins in modifying IGF actions. Ann N Y Acad Sci 692:10–21CrossRefPubMed

15.

Drop SL, Schuller AG, Lindenbergh-Kortleve DJ, Groffen C, Brinkman A, Zwarthoff EC (1992) Structural aspects of the IGFBP family. Growth Regul 2:69–79PubMed

16.

Fressinaud C, Jean I, Dubas F (2003) Selective decrease in axonal nerve growth factor and insulin-like growth factor I immunoreactivity in axonopathies of unknown etiology. Acta Neuropathol 105:477–483. doi:10.1007/s00401-002-0669-7 PubMed

17.

Giannini S, Cresci B, Manuelli C, Pala L, Rotella CM (2006) Diabetic microangiopathy: IGFBP control endothelial cell growth by a common mechanism in spite of their species specificity and tissue peculiarity. J Endocrinol Invest 29:754–763CrossRefPubMed

18.

Gundersen HJ (1978) Estimators of the number of objects per area unbiased by edge effects. Microsc Acta 81:107–117PubMed

19.

Hughes R, Bensa S, Willison H, Van den Bergh P, Comi G, Illa I, Nobile-Orazio E, van Doorn P, Dalakas M, Bojar M et al (2001) Randomized controlled trial of intravenous immunoglobulin versus oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy. Ann Neurol 50:195–201CrossRefPubMed

20.

Hughes RA, Sendtner M, Thoenen H (1993) Members of several gene families influence survival of rat motoneurons in vitro and in vivo. J Neurosci Res 36:663–671. doi:10.1002/jnr.490360607 CrossRefPubMed

21.

Kimura J (2001) Principles and variations of nerve conduction studies, and techniques to assess muscle function. In: Electrodiagnosis in diseases of nerve and muscle: principles and practice. Oxford University Press, New York, pp 91–117

22.

Jablonka S, Karle K, Sandner B, Andreassi C, von Au K, Sendtner M (2006) Distinct and overlapping alterations in motor and sensory neurons in a mouse model of spinal muscular atrophy. Hum Mol Genet 15:511–518. doi:10.1093/hmg/ddi467 CrossRefPubMed

23.

Jann S, Bramerio MA, Beretta S, Koch S, Defanti CA, Toyka KV, Sommer C (2003) Diagnostic value of sural nerve matrix metalloproteinase-9 in diabetic patients with CIDP. Neurology 61:1607–1610CrossRefPubMed

24.

Jones JI, Clemmons DR (1995) Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 16:3–34. doi:10.1210/edrv-16-1-3 PubMed

25.

Jones JI, Gockerman A, Busby WH Jr, Camacho-Hubner C, Clemmons DR (1993) Extracellular matrix contains insulin-like growth factor binding protein-5: potentiation of the effects of IGF-I. J Cell Biol 121:679–687CrossRefPubMed

26.

Kalus W, Zweckstetter M, Renner C, Sanchez Y, Georgescu J, Grol M, Demuth D, Schumacher R, Dony C, Lang K et al (1998) Structure of the IGF-binding domain of the insulin-like growth factor-binding protein-5 (IGFBP-5): implications for IGF and IGF-I receptor interactions. EMBO J 17:6558–6572. doi:10.1093/emboj/17.22.6558 CrossRefPubMedCentralPubMed

27.

Kelley KM, Oh Y, Gargosky SE, Gucev Z, Matsumoto T, Hwa V, Ng L, Simpson DM, Rosenfeld RG (1996) Insulin-like growth factor-binding proteins (IGFBPs) and their regulatory dynamics. Int J Biochem Cell Biol 28:619–637CrossRefPubMed

28.

Kimura J (2001) Techniques to assess muscle function. In: Electrodiagnosis in diseases of nerve and muscle: principles and practice. Oxford University Press, New York, pp 307–339

29.

Krieger F, Elflein N, Saenger S, Wirthgen E, Rak K, Frantz S, Hoeflich A, Toyka KV, Metzger F, Jablonka S (2014) Polyethylene glycol-coupled IGF1 delays motor function defects in a mouse model of spinal muscular atrophy with respiratory distress type 1. Brain 137:1374–1393. doi:10.1093/brain/awu059 CrossRefPubMed

30.

Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A (1993) Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 75:59–72PubMed

31.

Lobsiger CS, Boillee S, McAlonis-Downes M, Khan AM, Feltri ML, Yamanaka K, Cleveland DW (2009) Schwann cells expressing dismutase active mutant SOD1 unexpectedly slow disease progression in ALS mice. Proc Natl Acad Sci 106:4465–4470. doi:10.1073/pnas.0813339106 CrossRefPubMedCentralPubMed

32.

Moyer-Mileur LJ, Slater H, Jordan KC, Murray MA (2008) IGF-1 and IGF-binding proteins and bone mass, geometry, and strength: relation to metabolic control in adolescent girls with type 1 diabetes. J Bone Miner Res 23:1884–1891. doi:10.1359/jbmr.080713 CrossRefPubMedCentralPubMed

33.

Neff NT, Prevette D, Houenou LJ, Lewis ME, Glicksman MA, Yin QW, Oppenheim RW (1993) Insulin-like growth factors: putative muscle-derived trophic agents that promote motoneuron survival. J Neurobiol 24:1578–1588. doi:10.1002/neu.480241203 CrossRefPubMed

34.

Nyenwe EA, Jerkins TW, Umpierrez GE, Kitabchi AE (2011) Management of type 2 diabetes: evolving strategies for the treatment of patients with type 2 diabetes. Metab Clin Exp 60:1–23. doi:10.1016/j.metabol.2010.09.010 CrossRefPubMedCentralPubMed

35.

Park IS, Kiyomoto H, Alvarez F, Xu YC, Abboud HE, Abboud SL (1998) Preferential expression of insulin-like growth factor binding proteins-1, -3, and -5 during early diabetic renal hypertrophy in rats. Am J Kidney Dis 32:1000–1010CrossRefPubMed

36.

Pastore C, Izura V, Geijo-Barrientos E, Dominguez JR (1999) A comparison of electrophysiological tests for the early diagnosis of diabetic neuropathy. Muscle Nerve 22:1667–1673CrossRefPubMed

37.

Polydefkis M, Griffin JW, McArthur J (2003) New insights into diabetic polyneuropathy. JAMA 290:1371–1376. doi:10.1001/jama.290.10.1371 CrossRefPubMed

38.

Price GJ, Berka JL, Werther GA, Bach LA (1997) Cell-specific regulation of mRNAs for IGF-I and IGF-binding proteins-4 and -5 in streptozotocin-diabetic rat kidney. J Mol Endocrinol 18:5–14CrossRefPubMed

39.

Ramji N, Toth C, Kennedy J, Zochodne DW (2007) Does diabetes mellitus target motor neurons? Neurobiol Dis 26:301–311. doi:10.1016/j.nbd.2006.11.016 CrossRefPubMed

40.

Said G (2007) Diabetic neuropathy–a review. Nat Clin Pract Neurol 3:331–340. doi:10.1038/ncpneuro0504 CrossRefPubMed

41.

Schweizer U, Gunnersen J, Karch C, Wiese S, Holtmann B, Takeda K, Akira S, Sendtner M (2002) Conditional gene ablation of Stat3 reveals differential signaling requirements for survival of motoneurons during development and after nerve injury in the adult. J Cell Biol 156:287–297. doi:10.1083/jcb.200107009 CrossRefPubMedCentralPubMed

42.

Serbedzija P, Madl JE, Ishii DN (2009) Insulin and IGF-I prevent brain atrophy and DNA loss in diabetes. Brain Res 1303:179–194. doi:10.1016/j.brainres.2009.09.063 CrossRefPubMedCentralPubMed

43.

Song SE, Kim YW, Kim JY, Lee DH, Kim JR, Park SY (2013) IGFBP5 mediates high glucose-induced cardiac fibroblast activation. J Mol Endocrinol 50:291–303. doi:10.1530/JME-12-0194 CrossRefPubMed

44.

Stenvers KL, Zimmermann EM, Gallagher M, Lund PK (1994) Expression of insulin-like growth factor binding protein-4 and -5 mRNAs in adult rat forebrain. J Comp Neurol 339:91–105. doi:10.1002/cne.903390109 CrossRefPubMed

45.

Strotmeyer ES, de Rekeneire N, Schwartz AV, Faulkner KA, Resnick HE, Goodpaster BH, Shorr RI, Vinik AI, Harris TB, Newman AB (2008) The relationship of reduced peripheral nerve function and diabetes with physical performance in older white and black adults: the Health, Aging, and Body Composition (Health ABC) study. Diabetes Care 31:1767–1772. doi:10.2337/dc08-0433 CrossRefPubMedCentralPubMed

46.

Syroid DE, Zorick TS, Arbet-Engels C, Kilpatrick TJ, Eckhart W, Lemke G (1999) A role for insulin-like growth factor-I in the regulation of Schwann cell survival. J Neurosci 19:2059–2068PubMed

47.

Tan K, Baxter RC (1986) Serum insulin-like growth factor I levels in adult diabetic patients: the effect of age. J Clin Endocrinol Metab 63:651–655. doi:10.1210/jcem-63-3-651 CrossRefPubMed

48.

Trujillo-Hernandez B, Huerta M, Trujillo X, Vasquez C, Perez-Vargas D, Millan-Guerrero RO (2005) F-wave and H-reflex alterations in recently diagnosed diabetic patients. J Clin Neurosci 12:763–766. doi:10.1016/j.jocn.2004.09.018 CrossRefPubMed

49.

Uceyler N, Rogausch JP, Toyka KV, Sommer C (2007) Differential expression of cytokines in painful and painless neuropathies. Neurology 69:42–49. doi:10.1212/01.wnl.0000265062.92340.a5 CrossRefPubMed

50.

Vincent AM, Russell JW, Low P, Feldman EL (2004) Oxidative stress in the pathogenesis of diabetic neuropathy. Endocr Rev 25:612–628. doi:10.1210/er.2003-0019 CrossRefPubMed

51.

Wang H, Qin J, Gong S, Feng B, Zhang Y, Tao J (2014) Insulin-like growth factor-1 receptor-mediated inhibition of A-type K(+) current induces sensory neuronal hyperexcitability through the phosphatidylinositol 3-kinase and extracellular signal-regulated kinase 1/2 pathways, independently of Akt. Endocrinology 155:168–179. doi:10.1210/en.2013-1559 CrossRefPubMed

52.

Wiese S, Herrmann T, Drepper C, Jablonka S, Funk N, Klausmeyer A, Rogers ML, Rush R, Sendtner M (2010) Isolation and enrichment of embryonic mouse motoneurons from the lumbar spinal cord of individual mouse embryos. Nat Protoc 5:31–38. doi:10.1038/nprot.2009.193 CrossRefPubMed

53.

Wuarin L, Guertin DM, Ishii DN (1994) Early reduction in insulin-like growth factor gene expression in diabetic nerve. Exp Neurol 130:106–114. doi:10.1006/exnr.1994.1189 CrossRefPubMed

54.

Yamanaka Y, Wilson EM, Rosenfeld RG, Oh Y (1997) Inhibition of insulin receptor activation by insulin-like growth factor binding proteins. J Biol Chem 272:30729–30734CrossRefPubMed

55.

Ye P, Carson J, D’Ercole AJ (1995) In vivo actions of insulin-like growth factor-I (IGF-I) on brain myelination: studies of IGF-I and IGF binding protein-1 (IGFBP-1) transgenic mice. J Neurosci 15:7344–7356PubMed

56.

Zeslawski W, Beisel HG, Kamionka M, Kalus W, Engh RA, Huber R, Lang K, Holak TA (2001) The interaction of insulin-like growth factor-I with the N-terminal domain of IGFBP-5. EMBO J 20:3638–3644. doi:10.1093/emboj/20.14.3638 CrossRefPubMedCentralPubMed

57.

Zielasek J, Martini R, Toyka KV (1996) Functional abnormalities in P0-deficient mice resemble human hereditary neuropathies linked to P0 gene mutations. Muscle Nerve 19:946–952. doi:10.1002/(SICI)1097-4598(199608)19:8<946:AID-MUS2>3.0.CO;2-8 CrossRefPubMed

58.

Zylka MJ, Rice FL, Anderson DJ (2005) Topographically distinct epidermal nociceptive circuits revealed by axonal tracers targeted to Mrgprd. Neuron 45:17–25. doi:10.1016/j.neuron.2004.12.015 CrossRefPubMed

Title: Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy
Authors: 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
Publication date: 01-09-2015
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 3/2015
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-015-1446-8

At a glance: The STEP trials

Springer Medicine

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

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2015

TERT promoter mutations in primary central nervous system lymphoma are associated with spatial distribution in the splenium

Tau pathology spread in PS19 tau transgenic mice following locus coeruleus (LC) injections of synthetic tau fibrils is determined by the LC’s afferent and efferent connections

Molecular profiling of long-term survivors identifies a subgroup of glioblastoma characterized by chromosome 19/20 co-gain

High frequency of H3F3A K27M mutations characterizes pediatric and adult high-grade gliomas of the spinal cord

Semi-automated quantification of C9orf72 expansion size reveals inverse correlation between hexanucleotide repeat number and disease duration in frontotemporal degeneration

A new dopaminergic nigro-olfactory projection