Publisher Correction: NRG1 type I dependent autoparacrine stimulation of Schwann cells in onion bulbs of peripheral neuropathies

Fledrich, Robert; Akkermann, Dagmar; Schütza, Vlad; Abdelaal, Tamer A.; Hermes, Doris; Schäffner, Erik; Soto-Bernardini, Maria Clara; Götze, Tilmann; Klink, Axel; Kusch, Kathrin; Krueger, Martin; Kungl, Theresa; Frydrychowicz, Clara; Möbius, Wiebke; Brück, Wolfgang; Mueller, Wolf; Bechmann, Ingo; Sereda, Michael W.; Schwab, Markus H.; Nave, Klaus‐Armin; Stassart, Ruth M.

doi:10.1038/s41467-019-09886-4

Cited by 3 publications

(4 citation statements)

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“…The most common CMT form (CMT1A) is caused by an intrachromosomal duplication of the gene encoding for the "peripheral myelin protein of 22KD (PMP22)" (Lupski et al, 1991;Lupski & Garcia, 1992;Raeymaekers et al, 1991), a small myelin protein of unknown function (Li, Parker, Martyn, Natarajan, & Guo, 2013). Fifty percent overexpression of PMP22 causes peripheral nerve dysmyelination, axonal dysfunction, and loss and progressive muscle weakness in patients which can be well modeled in a Pmp22 transgenic rat model ("CMT1A rat") (Fledrich et al, 2014(Fledrich et al, , 2018(Fledrich et al, , 2019a(Fledrich et al, , 2019bMurphy et al, 2012;Rossor et al, 2015Rossor et al, , 2016Sereda et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Synergistic PXT3003 therapy uncouples neuromuscular function from dysmyelination in male Charcot–Marie–Tooth disease type 1A (CMT1A) rats

Prukop

Wernick

Boussicault

et al. 2020

J of Neuroscience Research

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Charcot–Marie–Tooth disease 1 A (CMT1A) is caused by an intrachromosomal duplication of the gene encoding for PMP22 leading to peripheral nerve dysmyelination, axonal loss, and progressive muscle weakness. No therapy is available. PXT3003 is a low‐dose combination of baclofen, naltrexone, and sorbitol which has been shown to improve disease symptoms in Pmp22 transgenic rats, a bona fide model of CMT1A disease. However, the superiority of PXT3003 over its single components or dual combinations have not been tested. Here, we show that in a dorsal root ganglion (DRG) co‐culture system derived from transgenic rats, PXT3003 induced myelination when compared to its single and dual components. Applying a clinically relevant (“translational”) study design in adult male CMT1A rats for 3 months, PXT3003, but not its dual components, resulted in improved performance in behavioral motor and sensory endpoints when compared to placebo. Unexpectedly, we observed only a marginally increased number of myelinated axons in nerves from PXT3003‐treated CMT1A rats. However, in electrophysiology, motor latencies correlated with increased grip strength indicating a possible effect of PXT3003 on neuromuscular junctions (NMJs) and muscle fiber pathology. Indeed, PXT3003‐treated CMT1A rats displayed an increased perimeter of individual NMJs and a larger number of functional NMJs. Moreover, muscles of PXT3003 CMT1A rats displayed less neurogenic atrophy and a shift toward fast contracting muscle fibers. We suggest that ameliorated motor function in PXT3003‐treated CMT1A rats result from restored NMJ function and muscle innervation, independent from myelination.

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Section: Introductionmentioning

confidence: 99%

Synergistic PXT3003 therapy uncouples neuromuscular function from dysmyelination in male Charcot–Marie–Tooth disease type 1A (CMT1A) rats

Prukop

Wernick

Boussicault

et al. 2020

J of Neuroscience Research

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“…CRD-NRG1 harbors 2 transmembrane domains ( figure 1A ) and signals to ErbB4, its main receptor in the brain. Here, we generated conditional transgenic mice ( Stop-Nrg1 ) for Cre-mediated expression of N-terminally hemagglutinin (HA) epitope-tagged CRD-NRG1 26 ( figure 1B ; supplementary figures 1A and 1B ). Based on “Stop” element-encoded GFP, we observed β-actin promoter-driven transgene expression in the brain and various organs ( supplementary figure 1C ; data not shown).…”

Section: Resultsmentioning

confidence: 99%

Hyperactivity is a Core Endophenotype of Elevated Neuregulin-1 Signaling in Embryonic Glutamatergic Networks

Götze

Soto-Bernardini

Zhang

et al. 2021

Schizophrenia Bulletin

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The neuregulin 1 (NRG1) ErbB4 module is at the core of an “at risk” signaling pathway in schizophrenia. Several human studies suggest hyperstimulation of NRG1-ErbB4 signaling as a plausible pathomechanism; however, little is known about the significance of stage-, brain area-, or neural cell type-specific NRG1-ErbB4 hyperactivity for disease-relevant brain endophenotypes. To address these spatiotemporal aspects, we generated transgenic mice for Cre recombinase-mediated overexpression of cystein-rich domain (CRD) NRG1, the most prominent NRG1 isoform in the brain. A comparison of “brain-wide” vs cell type-specific CRD-NRG1 overexpressing mice revealed that pathogenic CRD-NRG1 signals for ventricular enlargement and neuroinflammation originate outside glutamatergic neurons and suggests a subcortical function of CRD-NRG1 in the control of body weight. Embryonic onset of CRD-NRG1 in glutamatergic cortical networks resulted in reduced inhibitory neurotransmission and locomotor hyperactivity. Our findings identify ventricular enlargement and locomotor hyperactivity, 2 main endophenotypes of schizophrenia, as specific consequences of spatiotemporally distinct expression profiles of hyperactivated CRD-NRG1 signaling.

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“…Under NRG1 dysfunctional conditions neuronal degeneration and abnormal myelin thickness are observed [ 117 ]. NRG1 type I (NRG1-I) levels are upregulated in rodent models of CMT1A [ 59 , 85 ], while genetic ablation of SC-derived NRG1-I signaling in C61 mice inhibited hypermyelination and formation of onion bulbs and normalized the misbalanced ErbB2 receptor-MEK/ERK signaling leading to improved phenotype of the model [ 85 ].…”

Section: Emerging Treatments For Demyelinating Cmt Neuropathiesmentioning

confidence: 99%

“…Some approaches have also been evaluated in clinical trials, however at present there is no cure for CMT1A but only symptomatic treatment (Table 1). Nano-Cur Modified curcumin, anti-oxidant activity [81,82] Progesterone receptor antagonist (Onapristone) Inhibition of SCs myelin-related genes expression [83,84] NRG1 Paracrine growth factor, genetic ablation [85] Fasting and rapamycin Improve ER processing of overproduced PMP22 [86][87][88] Upregulation of c-Jun transcription factor Stimulates myelin gene expression [89,90] 3.1.1. Gene Therapy Approaches for CMT1A…”

Section: Emerging Treatments For Demyelinating Cmt Neuropathiesmentioning

confidence: 99%

Emerging Therapies for Charcot-Marie-Tooth Inherited Neuropathies

Stavrou

Sargiannidou

Georgiou

et al. 2021

IJMS

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Inherited neuropathies known as Charcot-Marie-Tooth (CMT) disease are genetically heterogeneous disorders affecting the peripheral nerves, causing significant and slowly progressive disability over the lifespan. The discovery of their diverse molecular genetic mechanisms over the past three decades has provided the basis for developing a wide range of therapeutics, leading to an exciting era of finding treatments for this, until now, incurable group of diseases. Many treatment approaches, including gene silencing and gene replacement therapies, as well as small molecule treatments are currently in preclinical testing while several have also reached clinical trial stage. Some of the treatment approaches are disease-specific targeted to the unique disease mechanism of each CMT form, while other therapeutics target common pathways shared by several or all CMT types. As promising treatments reach the stage of clinical translation, optimal outcome measures, novel biomarkers and appropriate trial designs are crucial in order to facilitate successful testing and validation of novel treatments for CMT patients.

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Publisher Correction: NRG1 type I dependent autoparacrine stimulation of Schwann cells in onion bulbs of peripheral neuropathies

Cited by 3 publications

References 0 publications

Synergistic PXT3003 therapy uncouples neuromuscular function from dysmyelination in male Charcot–Marie–Tooth disease type 1A (CMT1A) rats

Synergistic PXT3003 therapy uncouples neuromuscular function from dysmyelination in male Charcot–Marie–Tooth disease type 1A (CMT1A) rats

Hyperactivity is a Core Endophenotype of Elevated Neuregulin-1 Signaling in Embryonic Glutamatergic Networks

Emerging Therapies for Charcot-Marie-Tooth Inherited Neuropathies

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