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  - 
TY  - JOUR
A1  - Scholz, Nicole
A1  - Guan, Chonglin
A1  - Nieberler, Matthias
A1  - Grotmeyer, Alexander
A1  - Maiellaro, Isabella
A1  - Gao, Shiqiang
A1  - Beck, Sebastian
A1  - Pawlak, Matthias
A1  - Sauer, Markus
A1  - Asan, Esther
A1  - Rothemund, Sven
A1  - Winkler, Jana
A1  - Prömel, Simone
A1  - Nagel, Georg
A1  - Langenhan, Tobias
A1  - Kittel, Robert J
T1  - Mechano-dependent signaling by Latrophilin/CIRL quenches cAMP in proprioceptive neurons
JF  - eLife
N2  - Adhesion-type G protein-coupled receptors (aGPCRs), a large molecule family with over 30 members in humans, operate in organ development, brain function and govern immunological responses. Correspondingly, this receptor family is linked to a multitude of diverse human diseases. aGPCRs have been suggested to possess mechanosensory properties, though their mechanism of action is fully unknown. Here we show that the Drosophila aGPCR Latrophilin/dCIRL acts in mechanosensory neurons by modulating ionotropic receptor currents, the initiating step of cellular mechanosensation. This process depends on the length of the extended ectodomain and the tethered agonist of the receptor, but not on its autoproteolysis, a characteristic biochemical feature of the aGPCR family. Intracellularly, dCIRL quenches cAMP levels upon mechanical activation thereby specifically increasing the mechanosensitivity of neurons. These results provide direct evidence that the aGPCR dCIRL acts as a molecular sensor and signal transducer that detects and converts mechanical stimuli into a metabotropic response.
KW  - Latrophilin
KW  - adhesion GPCR
KW  - dCIRL
KW  - sensory physiology
KW  - metabotropic signalling
KW  - mechanotransduction
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170520
VL  - 6
IS  - e28360
ER  -