@article{MassihVehSchenkeetal.2023,
  author    = {Massih, Bita and Veh, Alexander and Schenke, Maren and Mungwa, Simon and Seeger, Bettina and Selvaraj, Bhuvaneish T. and Chandran, Siddharthan and Reinhardt, Peter and Sterneckert, Jared and Hermann, Andreas and Sendtner, Michael and L{\"u}ningschr{\"o}r, Patrick},
  title     = {A 3D cell culture system for bioengineering human neuromuscular junctions to model ALS},
  series = {Frontiers in Cell and Developmental Biology},
  volume    = {11},
  journal   = {Frontiers in Cell and Developmental Biology},
  issn      = {2296-634X},
  doi       = {10.3389/fcell.2023.996952},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304161},
  year      = {2023},
  abstract  = {The signals that coordinate and control movement in vertebrates are transmitted from motoneurons (MNs) to their target muscle cells at neuromuscular junctions (NMJs). Human NMJs display unique structural and physiological features, which make them vulnerable to pathological processes. NMJs are an early target in the pathology of motoneuron diseases (MND). Synaptic dysfunction and synapse elimination precede MN loss suggesting that the NMJ is the starting point of the pathophysiological cascade leading to MN death. Therefore, the study of human MNs in health and disease requires cell culture systems that enable the connection to their target muscle cells for NMJ formation. Here, we present a human neuromuscular co-culture system consisting of induced pluripotent stem cell (iPSC)-derived MNs and 3D skeletal muscle tissue derived from myoblasts. We used self-microfabricated silicone dishes combined with Velcro hooks to support the formation of 3D muscle tissue in a defined extracellular matrix, which enhances NMJ function and maturity. Using a combination of immunohistochemistry, calcium imaging, and pharmacological stimulations, we characterized and confirmed the function of the 3D muscle tissue and the 3D neuromuscular co-cultures. Finally, we applied this system as an in vitro model to study the pathophysiology of Amyotrophic Lateral Sclerosis (ALS) and found a decrease in neuromuscular coupling and muscle contraction in co-cultures with MNs harboring ALS-linked SOD1 mutation. In summary, the human 3D neuromuscular cell culture system presented here recapitulates aspects of human physiology in a controlled in vitro setting and is suitable for modeling of MND.},
  language  = {en}
}
@article{YadavSelvarajBenderetal.2016,
  author    = {Yadav, Preeti and Selvaraj, Bhuvaneish T. and Bender, Florian L. P. and Behringer, Marcus and Moradi, Mehri and Sivadasan, Rajeeve and Dombert, Benjamin and Blum, Robert and Asan, Esther and Sauer, Markus and Julien, Jean-Pierre and Sendtner, Michael},
  title     = {Neurofilament depletion improves microtubule dynamics via modulation of Stat3/stathmin signaling},
  series = {Acta Neuropathologica},
  volume    = {132},
  journal   = {Acta Neuropathologica},
  number    = {1},
  doi       = {10.1007/s00401-016-1564-y},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-188234},
  pages     = {93-110},
  year      = {2016},
  abstract  = {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.},
  language  = {en}
}