12073
2014
eng
668-82
3
137
article
1
2015-10-21
--
--
The Gdap1 knockout mouse mechanistically links redox control to Charcot–Marie–Tooth disease
The ganglioside-induced differentiation-associated protein 1 (GDAP1) is a mitochondrial fission factor and mutations in GDAP1 cause Charcot–Marie–Tooth disease. We found that Gdap1 knockout mice (\(Gdap1^{−/−}\)), mimicking genetic alterations of patients suffering from severe forms of Charcot–Marie–Tooth disease, develop an age-related, hypomyelinating peripheral neuropathy. Ablation of Gdap1 expression in Schwann cells recapitulates this phenotype. Additionally, intra-axonal mitochondria of peripheral neurons are larger in \(Gdap1^{−/−}\) mice and mitochondrial transport is impaired in cultured sensory neurons of \(Gdap1^{−/−}\) mice compared with controls. These changes in mitochondrial morphology and dynamics also influence mitochondrial biogenesis. We demonstrate that mitochondrial DNA biogenesis and content is increased in the peripheral nervous system but not in the central nervous system of \(Gdap1^{−/−}\) mice compared with control littermates. In search for a molecular mechanism we turned to the paralogue of GDAP1, GDAP1L1, which is mainly expressed in the unaffected central nervous system. GDAP1L1 responds to elevated levels of oxidized glutathione by translocating from the cytosol to mitochondria, where it inserts into the mitochondrial outer membrane. This translocation is necessary to substitute for loss of GDAP1 expression. Accordingly, more GDAP1L1 was associated with mitochondria in the spinal cord of aged \(Gdap1^{−/−}\) mice compared with controls. Our findings demonstrate that Charcot–Marie–Tooth disease caused by mutations in GDAP1 leads to mild, persistent oxidative stress in the peripheral nervous system, which can be compensated by GDAP1L1 in the unaffected central nervous system. We conclude that members of the GDAP1 family are responsive and protective against stress associated with increased levels of oxidized glutathione.
Brain
10.1093/brain/awt371
24480485
urn:nbn:de:bvb:20-opus-120731
Brain 2014: 137; 668–682. doi:10.1093/brain/awt371
Axel Niemann
Nina Huber
Konstanze M. Wagner
Christian Somandin
Michael Horn
Frédéric Lebrun-Julien
Brigitte Angst
Jorge A. Pereira
Hartmut Halfter
Hans Welzl
M. Laura Feltri
Lawrence Wrabetz
Peter Young
Carsten Wessig
Klaus V. Toyka
Ueli Suter
eng
uncontrolled
animal models
eng
uncontrolled
Charcot-Marie-Tooth disease
eng
uncontrolled
mitochondria
eng
uncontrolled
axonal transport
eng
uncontrolled
demyelinating disease
Medizin und Gesundheit
open_access
Neurologische Klinik und Poliklinik
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/12073/003_Niemann_Brain.pdf
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
13551
2013
eng
14
7
article
1
2016-06-27
--
--
Fatal atypical reversible posterior leukoencephalopathy syndrome: a case report
Introduction: Reversible posterior leukoencephalopathy syndrome – a reversible subacute global encephalopathy clinically presenting with headache, altered mental status, visual symptoms such as hemianopsia or cortical blindness, motor symptoms, and focal or generalized seizures – is characterized by a subcortical vasogenic edema symmetrically affecting posterior brain regions. Complete reversibility of both clinical signs and magnetic resonance imaging lesions is regarded as a defining feature of reversible posterior leukoencephalopathy syndrome. Reversible posterior leukoencephalopathy syndrome is almost exclusively seen in the setting of a predisposing clinical condition, such as pre-eclampsia, systemic infections, sepsis and shock, certain autoimmune diseases, various malignancies and cytotoxic chemotherapy, transplantation and concomitant immunosuppression (especially with calcineurin inhibitors) as well as episodes of abrupt hypertension. We describe for the first time clinical, radiological and histological findings in a case of reversible posterior leukoencephalopathy syndrome with an irreversible and fatal outcome occurring in the absence of any of the known predisposing clinical conditions except for a hypertensive episode.
Case presentation: A 58-year-old Caucasian woman presented with a two-week history of subacute and progressive occipital headache, blurred vision and imbalance of gait and with no evidence for raised arterial blood pressure during the two weeks previous to admission. Her past medical history was unremarkable except for controlled arterial hypertension. Cerebral magnetic resonance imaging demonstrated cortical and subcortical lesions with combined vasogenic and cytotoxic edema atypical for both venous congestion and arterial infarction. Routine laboratory and cerebrospinal fluid parameters were normal. The diagnosis of reversible posterior leukoencephalopathy syndrome was established.
Within hours after admission the patient showed a rapidly decreasing level of consciousness, extension and flexion synergisms, bilaterally extensor plantar responses and rapid cardiopulmonary decompensation requiring ventilatory and cardiocirculatory support. Follow-up cerebral imaging demonstrated widespread and confluent cytotoxic edematous lesions in different arterial territories, global cerebral swelling, and subsequent upper and lower brainstem herniation. Four days after admission, the patient was declared dead because of brain death.
Conclusion: This case demonstrates that fulminant and fatal reversible posterior leukoencephalopathy syndrome may occur spontaneously, that is, in the absence of any of the known predisposing systemic conditions.
Journal of Medical Case Reports
10.1186/1752-1947-7-14
urn:nbn:de:bvb:20-opus-135517
Journal of Medical Case Reports 2013, 7:14 doi:10.1186/1752-1947-7-14
Stefanie Kristin Golombeck
Carsten Wessig
Camelia-Maria Monoranu
Ansgar Schütz
Laszlo Solymosi
Nico Melzer
Christoph Kleinschnitz
eng
uncontrolled
reversible posterior leukoencephalopathy syndrome
eng
uncontrolled
generalized cerebral edema
eng
uncontrolled
cerebral autoregulation
eng
uncontrolled
blood pressure
Medizin und Gesundheit
open_access
Neurologische Klinik und Poliklinik
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/13551/055_Golombeck_Wessig_Monoranu.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
12945
2013
eng
14
7
article
1
2016-03-10
--
--
Fatal atypical reversible posterior leukoencephalopathy syndrome: a case report
Introduction: Reversible posterior leukoencephalopathy syndrome – a reversible subacute global encephalopathy clinically presenting with headache, altered mental status, visual symptoms such as hemianopsia or cortical blindness, motor symptoms, and focal or generalized seizures – is characterized by a subcortical vasogenic edema symmetrically affecting posterior brain regions. Complete reversibility of both clinical signs and magnetic resonance imaging lesions is regarded as a defining feature of reversible posterior leukoencephalopathy syndrome. Reversible posterior leukoencephalopathy syndrome is almost exclusively seen in the setting of a predisposing clinical condition, such as pre-eclampsia, systemic infections, sepsis and shock, certain autoimmune diseases, various malignancies and cytotoxic chemotherapy, transplantation and concomitant immunosuppression (especially with calcineurin inhibitors) as well as episodes of abrupt hypertension. We describe for the first time clinical, radiological and histological findings in a case of reversible posterior leukoencephalopathy syndrome with an irreversible and fatal outcome occurring in the absence of any of the known predisposing clinical conditions except for a hypertensive episode.
Case presentation: A 58-year-old Caucasian woman presented with a two-week history of subacute and progressive occipital headache, blurred vision and imbalance of gait and with no evidence for raised arterial blood pressure during the two weeks previous to admission. Her past medical history was unremarkable except for controlled arterial hypertension. Cerebral magnetic resonance imaging demonstrated cortical and subcortical lesions with combined vasogenic and cytotoxic edema atypical for both venous congestion and arterial infarction. Routine laboratory and cerebrospinal fluid parameters were normal. The diagnosis of reversible posterior leukoencephalopathy syndrome was established. Within hours after admission the patient showed a rapidly decreasing level of consciousness, extension and flexion synergisms, bilaterally extensor plantar responses and rapid cardiopulmonary decompensation requiring ventilatory and cardiocirculatory support. Follow-up cerebral imaging demonstrated widespread and confluent cytotoxic edematous lesions in different arterial territories, global cerebral swelling, and subsequent upper and lower brainstem herniation. Four days after admission, the patient was declared dead because of brain death.
Conclusion: This case demonstrates that fulminant and fatal reversible posterior leukoencephalopathy syndrome may occur spontaneously, that is, in the absence of any of the known predisposing systemic conditions.
Journal of Medical Case Reports
10.1186/1752-1947-7-14
urn:nbn:de:bvb:20-opus-129456
Journal of Medical Case Reports 2013, 7:14. DOI:10.1186/1752-1947-7-14
Stefanie Kristin Golombeck
Carsten Wessig
Camelia-Maria Monoranu
Ansgar Schütz
Laszlo Solymosi
Niko Melzer
Christoph Kleinschnitz
eng
uncontrolled
reversible posterior leukoencephalopathy syndrome
eng
uncontrolled
generalized cerebral edema
eng
uncontrolled
cerebral autoregulation
eng
uncontrolled
blood pressure
Medizin und Gesundheit
open_access
Neurologische Klinik und Poliklinik
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/12945/134_Golombeck_Journal_of_Medical_Case_Reports.pdf
11484
2014
eng
646-660
2
9
article
1
2015-06-25
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mTORC1 Controls PNS Myelination along the mTORC1-RXR gamma-SREBP-Lipid Biosynthesis Axis in Schwann Cells
Myelin formation during peripheral nervous system (PNS) development, and reformation after injury and in disease, requires multiple intrinsic and extrinsic signals. Akt/mTOR signaling has emerged as a major player involved, but the molecular mechanisms and downstream effectors are virtually unknown. Here, we have used Schwann-cell-specific conditional gene ablation of raptor and rictor, which encode essential components of the mTOR complexes 1 (mTORC1) and 2 (mTORC2), respectively, to demonstrate that mTORC1 controls PNS myelination during development. In this process, mTORC1 regulates lipid biosynthesis via sterol regulatory element-binding proteins (SREBPs). This course of action is mediated by the nuclear receptor RXRg, which transcriptionally regulates SREBP1c downstream of mTORC1. Absence of mTORC1 causes delayed myelination initiation as well as hypomyelination, together with abnormal lipid composition and decreased nerve conduction velocity. Thus, we have identified the mTORC1-RXR gamma-SREBP axis controlling lipid biosynthesis as a major contributor to proper peripheral nerve function.
Cell Reports
10.1016/j.celrep.2014.09.001
2211-1247
25310982
urn:nbn:de:bvb:20-opus-114847
Cell Reports 9, 646–660. DOI:10.1016/j.celrep.2014.09.001
Camilla Norrmen
Gianluca Figlia
Frederic Lebrun-Julien
Jorge A. Pereira
Martin Trötzmüller
Harald C. Köfeler
Ville Rantanen
Carsten Wessig
Anne-Lieke F. van Deijk
August B. Smit
Mark H. G. Verheijen
Markus A. Rüegg
Michael N. Hall
Ueli Suter
eng
uncontrolled
axonal integrity
eng
uncontrolled
peripheral nervous-system
eng
uncontrolled
COMPLEX 1
eng
uncontrolled
rat hepatocytes
eng
uncontrolled
SREBP
eng
uncontrolled
mice
eng
uncontrolled
growth
eng
uncontrolled
protein
eng
uncontrolled
element
eng
uncontrolled
CNS Myelination
Medizin und Gesundheit
open_access
Neurologische Klinik und Poliklinik
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/11484/023_Norrmen_Cell_Reports.pdf
https://opus.bibliothek.uni-wuerzburg.de/files/11484/023_Norrmen_Supplemental_Information.pdf
11523
2014
eng
e108756
10
9
article
1
2015-07-04
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FoxP3+Regulatory T Cells Determine Disease Severity in Rodent Models of Inflammatory Neuropathies
Inflammatory neuropathies represent disabling human autoimmune disorders with considerable disease variability. Animal models provide insights into defined aspects of their disease pathogenesis. Forkhead box P3 (FoxP3)+ regulatory T lymphocytes (Treg) are anti-inflammatory cells that maintain immune tolerance and counteract tissue damage in a variety of immune-mediated disorders. Dysfunction or a reduced frequency of Tregs have been associated with different human autoimmune disorders. We here analyzed the functional relevance of Tregs in determining disease manifestation and severity in murine models of autoimmune neuropathies. We took advantage of the DEREG mouse system allowing depletion of Treg with high specificity as well as anti-CD25 directed antibodies to deplete Tregs in mice in actively induced experimental autoimmune neuritis (EAN). Furthermore antibody-depletion was performed in an adoptive transfer model of chronic neuritis. Early Treg depletion increased clinical EAN severity both in active and adoptive transfer chronic neuritis. This was accompanied by increased proliferation of myelin specific T cells and histological signs of peripheral nerve inflammation. Late stage Treg depletion after initial disease manifestation however did not exacerbate inflammatory neuropathy symptoms further. We conclude that Tregs determine disease severity in experimental autoimmune neuropathies during the initial priming phase, but have no major disease modifying function after disease manifestation. Potential future therapeutic approaches targeting Tregs should thus be performed early in inflammatory neuropathies.
PLOS ONE
10.1371/journal.pone.0108756
urn:nbn:de:bvb:20-opus-115239
PLoS ONE 9(10): e108756. doi:10.1371/journal.pone.0108756
Gerd Meyer zu Hörste
Steffen Cordes
Anne K. Mausberg
Alla L. Zozulya
Carsten Wessig
Tim Sparwasser
Christian Mathys
Heinz Wiendl
Hans-Peter Hartung
Bernd C. Kieseier
eng
uncontrolled
Guillain-Barre-Syndrome
eng
uncontrolled
regulatory cells
eng
uncontrolled
C57BL/6 mice
eng
uncontrolled
demyelinating polyradiculoneuropathy
eng
uncontrolled
cytokines
eng
uncontrolled
pathogenesis
eng
uncontrolled
polyneuropathy
eng
uncontrolled
enteropathy
eng
uncontrolled
peptide
eng
uncontrolled
experimental autoimmune neuritis
Medizin und Gesundheit
open_access
Neurologische Klinik und Poliklinik
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/11523/036_Hoerste_PLOS_ONE.pdf