title: Soluble neuregulin-1 modulates disease pathogenesis in rodent models of Charcot-Marie-Tooth disease 1A.
abstract: Duplication of the gene encoding the peripheral myelin protein of 22 kDa (PMP22) underlies the most common inherited neuropathy, Charcot-Marie-Tooth 1A (CMT1A), a disease without a known cure. Although demyelination represents a characteristic feature, the clinical phenotype of CMT1A is determined by the degree of axonal loss, and patients suffer from progressive muscle weakness and impaired sensation. CMT1A disease manifests within the first two decades of life, and walking disabilities, foot deformities and electrophysiological abnormalities are already present in childhood. Here, we show in Pmp22-transgenic rodent models of CMT1A that Schwann cells acquire a persistent differentiation defect during early postnatal development, caused by imbalanced activity of the PI3K-Akt and the Mek-Erk signaling pathways. We demonstrate that enhanced PI3K-Akt signaling by axonally overexpressed neuregulin-1 (NRG1) type I drives diseased Schwann cells toward differentiation and preserves peripheral nerve axons. Notably, in a preclinical experimental therapy using a CMT1A rat model, when treatment is restricted to early postnatal development, soluble NRG1 effectively overcomes impaired peripheral nerve development and restores axon survival into adulthood. Our findings suggest a model in which Schwann cell differentiation within a limited time window is crucial for the long-term maintenance of axonal support.
authors.affiliation: 1] Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany. [2].
authors.forename: Robert
authors.initials: R
authors.lastname: Fledrich
authors.affiliation: 1] Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany. [2] Institute of Neuropathology, University Medical Center Göttingen, Göttingen, Germany. [3].
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Stassart
authors.affiliation: Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Klink
authors.affiliation: Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Lennart M
authors.initials: LM
authors.lastname: Rasch
authors.affiliation: 1] Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany. [2] Institute of Clinical Pharmacology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Prukop
authors.affiliation: Department of Clinical Neurophysiology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Lauren
authors.initials: L
authors.lastname: Haag
authors.affiliation: Department of Clinical Neurophysiology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Czesnik
authors.affiliation: Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Theresa
authors.initials: T
authors.lastname: Kungl
authors.affiliation: Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Tamer A M
authors.initials: TA
authors.lastname: Abdelaal
authors.affiliation: 1] Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany. [2] Department of Neurosurgery, University Medical Center, Johannes-Gutenberg University of Mainz, Mainz, Germany.
authors.forename: Naureen
authors.initials: N
authors.lastname: Keric
authors.affiliation: Institute of Neuropathology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Stadelmann
authors.affiliation: Institute of Neuropathology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Brück
authors.affiliation: Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Klaus-Armin
authors.initials: KA
authors.lastname: Nave
authors.affiliation: 1] Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany. [2] Department of Clinical Neurophysiology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Sereda
mesh_terms: D000818:Animals; D002607:Charcot-Marie-Tooth Disease / Q000503:physiopathology*; D004195:Disease Models, Animal; D008297:Male; D020890:Neuregulin-1 / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D055647:Rats, Transgenic
chemical_list: D020890:Neuregulin-1; C490580:Nrg1 protein, rat; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt