TY  - THES
A1  - Thangaraj Selvaraj, Bhuvaneish
T1  - Role of CNTF-STAT3 signaling for microtubule dynamics inaxon growth and maintenance: Implications in motoneuron diseases
T1  - Die Funktion des CNTF-STAT3 Signalweges für die Microtubuli Dynamik in Axonalem Wachstum und Axon Erhalt: Implikationen für Motoneuronenerkrankungen
N2  - Neurotrophic factor signaling modulates differentiation, axon growth and maintenance, synaptic plasticity and regeneration of neurons after injury. Ciliary neurotrophic factor (CNTF), a Schwann cell derived neurotrophic factor, has an exclusive role in axon maintenance, sprouting and synaptic preservation. CNTF, but not GDNF, has been shown to alleviate motoneuron degeneration in pmn mutant mice carrying a missense mutation in Tbce gene, a model for Amyotrophic Lateral Sclerosis (ALS). This current study elucidates the distinct signaling mechanism by which CNTF rescues the axonal degeneration in pmn mutant mice. ...
N2  - Neurotrophe Faktoren beeinflussendie die neuronale Differenzierung, das Wachstum und die Stabilisierung von Axonen sowie Synaptische Plastizität und die Regeneration von Neuronen nach Verletzung. Der von Schwannzellen synthetisierte neurotrophe Faktor Ciliary neurotrophic factor (CNTF) spielt eine wichtige Rolle bei der axonalen Erhaltung sowie bei der Induktion und Reduktion von axonalen Verzweigungen. Die Behandlung der pmn Mausmutante mit CNTF, aber nicht mit GDNF führt zu einem späteren Krankheitsbeginn und verminderten Fortschreiten der Motoneuronendegeneration. Diese Mausmutante, die eine Punktmutation im Tbce Gen trägt, dient als Modell für die Amyotrophe Lateralsklerose. Ziel der vorliegenden Arbeit war es, die zugrunde liegenden Signalkaskaden aufzudecken, die den CNTF-vermittelten Effekt auf den Krnakheitsverlauf bei der pmn Maus verursachen. ...
KW  - Ciliary neurotrophic factor
KW  - STAT
KW  - CNTF
KW  - STAT3
KW  - Stathmin
KW  - Microtubules
KW  - Signaltransduktion
KW  - Motoneuron
KW  - Krankheit
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-76889
ER  - 
TY  - JOUR
A1  - Yadav, Preeti
A1  - Selvaraj, Bhuvaneish T.
A1  - Bender, Florian L. P.
A1  - Behringer, Marcus
A1  - Moradi, Mehri
A1  - Sivadasan, Rajeeve
A1  - Dombert, Benjamin
A1  - Blum, Robert
A1  - Asan, Esther
A1  - Sauer, Markus
A1  - Julien, Jean-Pierre
A1  - Sendtner, Michael
T1  - Neurofilament depletion improves microtubule dynamics via modulation of Stat3/stathmin signaling
JF  - Acta Neuropathologica
N2  - In neurons, microtubules form a dense array within axons, and the stability and function of this microtubule network is modulated by neurofilaments. Accumulation of neurofilaments has been observed in several forms of neurodegenerative diseases, but the mechanisms how elevated neurofilament levels destabilize axons are unknown so far. Here, we show that increased neurofilament expression in motor nerves of pmn mutant mice, a model of motoneuron disease, causes disturbed microtubule dynamics. The disease is caused by a point mutation in the tubulin-specific chaperone E (Tbce) gene, leading to an exchange of the most C-terminal amino acid tryptophan to glycine. As a consequence, the TBCE protein becomes instable which then results in destabilization of axonal microtubules and defects in axonal transport, in particular in motoneurons. Depletion of neurofilament increases the number and regrowth of microtubules in pmn mutant motoneurons and restores axon elongation. This effect is mediated by interaction of neurofilament with the stathmin complex. Accumulating neurofilaments associate with stathmin in axons of pmn mutant motoneurons. Depletion of neurofilament by Nefl knockout increases Stat3-stathmin interaction and stabilizes the microtubules in pmn mutant motoneurons. Consequently, counteracting enhanced neurofilament expression improves axonal maintenance and prolongs survival of pmn mutant mice. We propose that this mechanism could also be relevant for other neurodegenerative diseases in which neurofilament accumulation and loss of microtubules are prominent features.
KW  - Amyotrophic-lateral-sclerosis
KW  - Transgenic mice
KW  - Mouse model
KW  - Alzheimers disease
KW  - Neurofilament
KW  - Progressive motor neuronopathy
KW  - Axonal transport
KW  - Intermediate filaments
KW  - Motoneuron disease
KW  - Lacking neurofilaments
KW  - Missense mutation
KW  - Axon degeneration
KW  - Microtubules
KW  - Stathmin
KW  - Stat3
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188234
VL  - 132
IS  - 1
ER  -