12539
2012
eng
3567-3583
135
article
1
2016-01-26
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Myelin is dependent on the Charcot–Marie–Tooth Type 4H disease culprit protein FRABIN/FGD4 in Schwann cells
Studying the function and malfunction of genes and proteins associated with inherited forms of peripheral neuropathies has provided multiple clues to our understanding of myelinated nerves in health and disease. Here, we have generated a mouse model for the peripheral neuropathy Charcot–Marie–Tooth disease type 4H by constitutively disrupting the mouse orthologue of the suspected culprit gene FGD4 that encodes the small RhoGTPase Cdc42-guanine nucleotide exchange factor Frabin. Lack of Frabin/Fgd4 causes dysmyelination in mice in early peripheral nerve development, followed by profound myelin abnormalities and demyelination at later stages. At the age of 60 weeks, this was accompanied by electrophysiological deficits. By crossing mice carrying alleles of Frabin/Fgd4 flanked by loxP sequences with animals expressing Cre recombinase in a cell type-specific manner, we show that Schwann cell-autonomous Frabin/Fgd4 function is essential for proper myelination without detectable primary contributions from neurons. Deletion of Frabin/Fgd4 in Schwann cells of fully myelinated nerve fibres revealed that this protein is not only required for correct nerve development but also for accurate myelin maintenance. Moreover, we established that correct activation of Cdc42 is dependent on Frabin/Fgd4 function in healthy peripheral nerves. Genetic disruption of Cdc42 in Schwann cells of adult myelinated nerves resulted in myelin alterations similar to those observed in Frabin/Fgd4-deficient mice, indicating that Cdc42 and the Frabin/Fgd4–Cdc42 axis are critical for myelin homeostasis. In line with known regulatory roles of Cdc42, we found that Frabin/Fgd4 regulates Schwann cell endocytosis, a process that is increasingly recognized as a relevant mechanism in peripheral nerve pathophysiology. Taken together, our results indicate that regulation of Cdc42 by Frabin/Fgd4 in Schwann cells is critical for the structure and function of the peripheral nervous system. In particular, this regulatory link is continuously required in adult fully myelinated nerve fibres. Thus, mechanisms regulated by Frabin/Fgd4–Cdc42 are promising targets that can help to identify additional regulators of myelin development and homeostasis, which may crucially contribute also to malfunctions in different types of peripheral neuropathies.
Brain
10.1093/brain/aws275
23171661
urn:nbn:de:bvb:20-opus-125390
Brain 2012: 135; 3567–3583. doi:10.1093/brain/aws275
Michael Horn
Reto Baumann
Jorge A. Pereira
Páris N. M. Sidiropoulos
Christian Somandin
Hans Welzl
Claudia Stendel
Tessa Lühmann
Carsten Wessig
Klaus V. Toyka
João B. Relvas
Jan Senderek
Ueli Suter
eng
uncontrolled
Frabin/Fgd4
eng
uncontrolled
myelination
eng
uncontrolled
hereditary motor and sensory neuropathy
eng
uncontrolled
Charcot–Marie–Tooth disease
eng
uncontrolled
Rho-GTPase Cdc42
Krankheiten
open_access
Neurologische Klinik und Poliklinik
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/12539/Abdelmohsen_Genome Announc.-2015-Horn.pdf
12341
2012
eng
349046
2012
article
1
2015-12-17
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In vitro contracture test results and anaesthetic management of a patient with emery-dreifuss muscular dystrophy for cardiac transplantation
Emery-Dreifuss muscular dystrophy (EDMD) is a hereditary neuromuscular disorder characterized by slowly progressive muscle weakness, early contractures, and dilated cardiomyopathy. We reported an uneventful general anaesthesia using total intravenous anaesthesia (TIVA) for cardiac transplantation in a 19-year-old woman suffering from EDMD. In vitro contracture test results of two pectoralis major muscle bundles of the patient suggest that exposition to triggering agents does not induce a pathological sarcoplasmic calcium release in the lamin A/C phenotype. However, due to the lack of evidence in the literature, we would recommend TIVA for patients with EDMD if general anaesthesia is required.
Case Reports in Anesthesiology
10.1155/2012/349046
PMC3438720
urn:nbn:de:bvb:20-opus-123413
Case Reports in Anesthesiology. 2012:349046. doi:10.1155/2012/349046
Frank Schuster
Carsten Wessig
Christoph Schimmer
Stephan Johannsen
Marc Lazarus
Ivan Aleksic
Rainer Leyh
Norbert Roewer
eng
uncontrolled
Emery-Dreifuss muscular dystrophy
Chirurgie und verwandte medizinische Fachrichtungen
open_access
Klinik und Poliklinik für Anästhesiologie (ab 2004)
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/12341/349046.pdf
13025
2012
eng
e37885
6
7
article
1
2016-03-18
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A Randomized, Double Blind, Placebo-Controlled Trial of Pioglitazone in Combination with Riluzole in Amyotrophic Lateral Sclerosis
Background: Pioglitazone, an oral anti-diabetic that stimulates the PPAR-gamma transcription factor, increased survival of mice with amyotrophic lateral sclerosis (ALS).
Methods/Principal Findings: We performed a phase II, double blind, multicentre, placebo controlled trial of pioglitazone in ALS patients under riluzole. 219 patients were randomly assigned to receive 45 mg/day of pioglitazone or placebo (one: one allocation ratio). The primary endpoint was survival. Secondary endpoints included incidence of non-invasive ventilation and tracheotomy, and slopes of ALS-FRS, slow vital capacity, and quality of life as assessed using EUROQoL EQ-5D. The study was conducted under a two-stage group sequential test, allowing to stop for futility or superiority after interim analysis. Shortly after interim analysis, 30 patients under pioglitazone and 24 patients under placebo had died. The trial was stopped for futility; the hazard ratio for primary endpoint was 1.21 (95% CI: 0.71-2.07, p = 0.48). Secondary endpoints were not modified by pioglitazone treatment. Pioglitazone was well tolerated.
Conclusion/Significance: Pioglitazone has no beneficial effects on the survival of ALS patients as add-on therapy to riluzole.
PLoS One
10.1371/journal.pone.0037885
urn:nbn:de:bvb:20-opus-130255
PLoS ONE 7(6): e37885. doi:10.1371/journal.pone.0037885
Luc Dupuis
Reinhard Dengler
Michael T. Heneka
Thomas Meyer
Stephan Zierz
Jan Kassubek
Wilhelm Fischer
Franziska Steiner
Eva Lindauer
Markus Otto
Jens Dreyhaupt
Torsten Grehl
Andreas Hermann
Andrea S. Winkler
Ulrich Bogdahn
Reiner Benecke
Bertold Schrank
Carsten Wessig
Julian Grosskreutz
Albert C. Ludolph
eng
uncontrolled
ALS
eng
uncontrolled
transgenic mouse model
eng
uncontrolled
central nervous system
eng
uncontrolled
nonalcoholic steatohepatitis
eng
uncontrolled
PPAR-gamme
eng
uncontrolled
hexanucleotide repeat
eng
uncontrolled
disease progression
eng
uncontrolled
delays progression
eng
uncontrolled
SOD1 mutations
eng
uncontrolled
monocycline
Medizin und Gesundheit
open_access
Neurologische Klinik und Poliklinik
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/13025/journal.pone.0037885.pdf