title: Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy.
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.
authors.affiliation: Institute for Clinical Neurobiology, University of Würzburg, Versbacher-Str. 5, 97078, Würzburg, Germany.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Simon
authors.forename: Stefanie
authors.initials: S
authors.lastname: Rauskolb
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Gunnersen
authors.forename: Bettina
authors.initials: B
authors.lastname: Holtmann
authors.forename: Carsten
authors.initials: C
authors.lastname: Drepper
authors.forename: Benjamin
authors.initials: B
authors.lastname: Dombert
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Braga
authors.forename: Stefan
authors.initials: S
authors.lastname: Wiese
authors.forename: Sibylle
authors.initials: S
authors.lastname: Jablonka
authors.forename: Dirk
authors.initials: D
authors.lastname: Pühringer
authors.forename: Jürgen
authors.initials: J
authors.lastname: Zielasek
authors.forename: Andreas
authors.initials: A
authors.lastname: Hoeflich
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Silani
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
authors.forename: Susanne
authors.initials: S
authors.lastname: Kneitz
authors.forename: Claudia
authors.initials: C
authors.lastname: Sommer
authors.forename: Klaus V
authors.initials: KV
authors.lastname: Toyka
authors.forename: Michael
authors.initials: M
authors.lastname: Sendtner
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism*; D049108:Cell Enlargement; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000503:physiopathology*; D003929:Diabetic Neuropathies / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D009046:Motor Neurons / Q000473:pathology / Q000502:physiology*; D009410:Nerve Degeneration / Q000473:pathology / Q000503:physiopathology*; D010791:Phrenic Nerve / Q000473:pathology / Q000503:physiopathology; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D012584:Sciatic Nerve / Q000473:pathology / Q000503:physiopathology; D012677:Sensation / Q000502:physiology
chemical_list: D002352:Carrier Proteins; C000607595:IGFBP5-interacting protein, mouse; D017526:Receptor, IGF Type 1