In patients with Charcot-Marie-Tooth disease 1A (CMT1A), peripheral nerves display aberrant myeli... more In patients with Charcot-Marie-Tooth disease 1A (CMT1A), peripheral nerves display aberrant myelination during postnatal development, followed by slowly progressive demyelination and axonal loss during adult life. Here, we show that myelinating Schwann cells in a rat model of CMT1A exhibit a developmental defect that includes reduced transcription of genes required for myelin lipid biosynthesis. Consequently, lipid incorporation into myelin is reduced, leading to an overall distorted stoichiometry of myelin proteins and lipids with ultrastructural changes of the myelin sheath. Substitution of phosphatidylcholine and phosphatidylethanolamine in the diet is sufficient to overcome the myelination deficit of affected Schwann cells in vivo. This treatment rescues the number of myelinated axons in the peripheral nerves of the CMT rats and leads to a marked amelioration of neuropathic symptoms. We propose that lipid supplementation is an easily translatable potential therapeutic approach i...
Introduction: Charcot-Marie-Tooth disease 1A (CMT1A) is the most common inherited neuropathy, cau... more Introduction: Charcot-Marie-Tooth disease 1A (CMT1A) is the most common inherited neuropathy, caused by a duplication of the gene encoding for the peripheral myelin protein of 22kDA (PMP22). Histologically, peripheral nerves of patients affected by CMT1A demonstrate a characteristic Schwann cell pathology,[for full text, please go to the a.m. URL]
Pm p2 2 t g Pm p2 2 t g x Nr g1 (I) tg h R el . m R N A (A U ) cJun phase Peripherin DAPI Merge S... more Pm p2 2 t g Pm p2 2 t g x Nr g1 (I) tg h R el . m R N A (A U ) cJun phase Peripherin DAPI Merge Soluble Neuregulin-1 promotes Schwann cell differentiation in Charcot-Marie-Tooth disease 1A Robert Fledrich, Ruth M. Stassart, Axel Klink, Lennart M. Rasch, Thomas Prukop, Lauren Haag, Dirk Czesnik, Theresa Kungl, Tamer A.M. Abdelaal, Naureen Keric, Christine Stadelmann, Wolfgang Brück, Klaus–Armin Nave and Michael W. Sereda
In contrast to acute peripheral nerve injury, the molecular response of Schwann cells in chronic ... more In contrast to acute peripheral nerve injury, the molecular response of Schwann cells in chronic neuropathies remains poorly understood. Onion bulb structures are a pathological hallmark of demyelinating neuropathies, but the nature of these formations is unknown. Here, we show that Schwann cells induce the expression of Neuregulin-1 type I (NRG1-I), a paracrine growth factor, in various chronic demyelinating diseases. Genetic disruption of Schwann cell-derived NRG1 signalling in a mouse model of Charcot-Marie-Tooth Disease 1A (CMT1A), suppresses hypermyelination and the formation of onion bulbs. Transgenic overexpression of NRG1-I in Schwann cells on a wildtype background is sufficient to mediate an interaction between Schwann cells via an ErbB2 receptor-MEK/ERK signaling axis, which causes onion bulb formations and results in a peripheral neuropathy reminiscent of CMT1A. We suggest that diseased Schwann cells mount a regeneration program that is beneficial in acute nerve injury, but that overstimulation of Schwann cells in chronic neuropathies is detrimental.
Charcot-Marie-Tooth disease is the most common inherited neuropathy and a duplication of the peri... more Charcot-Marie-Tooth disease is the most common inherited neuropathy and a duplication of the peripheral myelin protein 22 gene (PMP22) causes the most frequent sub-form Charcot-Marie-Tooth 1A (CMT1A). In contrary to the notion that CMT1A manifests in the second decade of life, moderate walking disability and electrophysiological abnormalities are usually already present during childhood. The early onset and developmental nature of the disease is also supported by findings derived from a Pmp22 transgenic rat model for CMT1A (CMT rat), which displays a reduced number of myelinated fibers per peripheral nerve already early postnatally and never reaches a wildtype level throughout development. RNA transcription analysis has revealed that there is a striking continuous upregulation of Schwan cell neuregulin 1 type I (NRG1_I) which we could show that it is contributing to the reported hypermyelination of small caliber axons in CMT1A rodent models. On the other hand, CMT rat Schwann cells show a strongly impaired lipid biogenesis required for myelination as assessed by RNA expression and lipid profiling of peripheral nerve transcriptomes and myelin composition, respectively. Importantly, Pmp22 overexpressing Schwann cell also reflects an impaired myelination competence in vitro, when co-cultured with dorsal root ganglia neurons. A remarkable improvement of Schwann cell myelination upon supplementation with phosphatidylcholine in vitro has led to the hypothesis that exogenous supplementation with lipids in vivo may improve disease progression. Indeed, we observed improved disease progression on the histological, electrophysiological and behavioral levels in CMT rats which were fed with a chow enriched in lecithin from P2 to adulthood. Moreover, disease amelioration is also visible after late long term (P21-P112) and early short term treatment (P2 to P21), but the effect is fading after treatment cessation. Therefore, continuously supplying patients with exogenous lipids may be considered as a promising therapeutic approach for CMT1A disease. Figure 1:The Schwann cell developmental lineage and repair response. The diagram shows the main developmental cell types, repair (Bungner) Schwann cell and steps of Schwann cell development. Solid arrows indicate developmental steps. Red arrows indicate Schwann cell injury associated transformation into repair cell. Dashed arrows indicate post-repair response. E stands for embryonic time points in mouse development. (Adapted from K. R. Jessen and R. Mirsky (2016). Figure 2:Schematic structures of major NRG1 isoforms in the nervous system. Unlike type III isoform, has two transmembrane domains, other isoforms (I&II) have only one transmembrane domain. Proteolytic cleavage in the juxta-membrane area releases the epidermal growth factor (EGF) domain containing part of both I&II isoforms while III remain anchored to the membrane. Adaptaed from Jessen & Mirsky 2005. All oligonucleotides were synthesized by the AGCT-laboratory of the Max Planck Institute for Experimental Medicine.
In patients with Charcot-Marie-Tooth disease 1A (CMT1A), peripheral nerves display aberrant myeli... more In patients with Charcot-Marie-Tooth disease 1A (CMT1A), peripheral nerves display aberrant myelination during postnatal development, followed by slowly progressive demyelination and axonal loss during adult life. Here, we show that myelinating Schwann cells in a rat model of CMT1A exhibit a developmental defect that includes reduced transcription of genes required for myelin lipid biosynthesis. Consequently, lipid incorporation into myelin is reduced, leading to an overall distorted stoichiometry of myelin proteins and lipids with ultrastructural changes of the myelin sheath. Substitution of phosphatidylcholine and phosphatidylethanolamine in the diet is sufficient to overcome the myelination deficit of affected Schwann cells in vivo. This treatment rescues the number of myelinated axons in the peripheral nerves of the CMT rats and leads to a marked amelioration of neuropathic symptoms. We propose that lipid supplementation is an easily translatable potential therapeutic approach i...
Introduction: Charcot-Marie-Tooth disease 1A (CMT1A) is the most common inherited neuropathy, cau... more Introduction: Charcot-Marie-Tooth disease 1A (CMT1A) is the most common inherited neuropathy, caused by a duplication of the gene encoding for the peripheral myelin protein of 22kDA (PMP22). Histologically, peripheral nerves of patients affected by CMT1A demonstrate a characteristic Schwann cell pathology,[for full text, please go to the a.m. URL]
Pm p2 2 t g Pm p2 2 t g x Nr g1 (I) tg h R el . m R N A (A U ) cJun phase Peripherin DAPI Merge S... more Pm p2 2 t g Pm p2 2 t g x Nr g1 (I) tg h R el . m R N A (A U ) cJun phase Peripherin DAPI Merge Soluble Neuregulin-1 promotes Schwann cell differentiation in Charcot-Marie-Tooth disease 1A Robert Fledrich, Ruth M. Stassart, Axel Klink, Lennart M. Rasch, Thomas Prukop, Lauren Haag, Dirk Czesnik, Theresa Kungl, Tamer A.M. Abdelaal, Naureen Keric, Christine Stadelmann, Wolfgang Brück, Klaus–Armin Nave and Michael W. Sereda
In contrast to acute peripheral nerve injury, the molecular response of Schwann cells in chronic ... more In contrast to acute peripheral nerve injury, the molecular response of Schwann cells in chronic neuropathies remains poorly understood. Onion bulb structures are a pathological hallmark of demyelinating neuropathies, but the nature of these formations is unknown. Here, we show that Schwann cells induce the expression of Neuregulin-1 type I (NRG1-I), a paracrine growth factor, in various chronic demyelinating diseases. Genetic disruption of Schwann cell-derived NRG1 signalling in a mouse model of Charcot-Marie-Tooth Disease 1A (CMT1A), suppresses hypermyelination and the formation of onion bulbs. Transgenic overexpression of NRG1-I in Schwann cells on a wildtype background is sufficient to mediate an interaction between Schwann cells via an ErbB2 receptor-MEK/ERK signaling axis, which causes onion bulb formations and results in a peripheral neuropathy reminiscent of CMT1A. We suggest that diseased Schwann cells mount a regeneration program that is beneficial in acute nerve injury, but that overstimulation of Schwann cells in chronic neuropathies is detrimental.
Charcot-Marie-Tooth disease is the most common inherited neuropathy and a duplication of the peri... more Charcot-Marie-Tooth disease is the most common inherited neuropathy and a duplication of the peripheral myelin protein 22 gene (PMP22) causes the most frequent sub-form Charcot-Marie-Tooth 1A (CMT1A). In contrary to the notion that CMT1A manifests in the second decade of life, moderate walking disability and electrophysiological abnormalities are usually already present during childhood. The early onset and developmental nature of the disease is also supported by findings derived from a Pmp22 transgenic rat model for CMT1A (CMT rat), which displays a reduced number of myelinated fibers per peripheral nerve already early postnatally and never reaches a wildtype level throughout development. RNA transcription analysis has revealed that there is a striking continuous upregulation of Schwan cell neuregulin 1 type I (NRG1_I) which we could show that it is contributing to the reported hypermyelination of small caliber axons in CMT1A rodent models. On the other hand, CMT rat Schwann cells show a strongly impaired lipid biogenesis required for myelination as assessed by RNA expression and lipid profiling of peripheral nerve transcriptomes and myelin composition, respectively. Importantly, Pmp22 overexpressing Schwann cell also reflects an impaired myelination competence in vitro, when co-cultured with dorsal root ganglia neurons. A remarkable improvement of Schwann cell myelination upon supplementation with phosphatidylcholine in vitro has led to the hypothesis that exogenous supplementation with lipids in vivo may improve disease progression. Indeed, we observed improved disease progression on the histological, electrophysiological and behavioral levels in CMT rats which were fed with a chow enriched in lecithin from P2 to adulthood. Moreover, disease amelioration is also visible after late long term (P21-P112) and early short term treatment (P2 to P21), but the effect is fading after treatment cessation. Therefore, continuously supplying patients with exogenous lipids may be considered as a promising therapeutic approach for CMT1A disease. Figure 1:The Schwann cell developmental lineage and repair response. The diagram shows the main developmental cell types, repair (Bungner) Schwann cell and steps of Schwann cell development. Solid arrows indicate developmental steps. Red arrows indicate Schwann cell injury associated transformation into repair cell. Dashed arrows indicate post-repair response. E stands for embryonic time points in mouse development. (Adapted from K. R. Jessen and R. Mirsky (2016). Figure 2:Schematic structures of major NRG1 isoforms in the nervous system. Unlike type III isoform, has two transmembrane domains, other isoforms (I&II) have only one transmembrane domain. Proteolytic cleavage in the juxta-membrane area releases the epidermal growth factor (EGF) domain containing part of both I&II isoforms while III remain anchored to the membrane. Adaptaed from Jessen & Mirsky 2005. All oligonucleotides were synthesized by the AGCT-laboratory of the Max Planck Institute for Experimental Medicine.
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