TY - JOUR A1 - Sendtner, Michael A1 - Thoenen, Hans T1 - Oxidative stress and motorneuron disease N2 - Transgenic mice carrying mutated Cu/Zn superoxide dismutase genes provide insights into the pathogenesis of human motorneuron diseases and may be useful as models in the development and testing of therapies. Y1 - 1994 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-42684 ER - TY - JOUR A1 - Sendtner, Michael A1 - Stöckli, Kurt A. A1 - Carroll, Patrick A1 - Kreutzberg, Georg W. A1 - Thoenen, Hans T1 - More on motor neurons N2 - No abstract available Y1 - 1992 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-42598 ER - TY - JOUR A1 - Lillien, Laura E. A1 - Sendtner, Michael A1 - Raff, Martin C. T1 - Extracellular Matrix-associated molecules collaborate with ciliary neurotrophic factor to induce type-2 astrocyte development N2 - 0-2A progenitor cells give rise to both oligodendrocytes and type-2 astrocytes in vitro. Whereas oligodendrocyte differentiation occurs constitutively, type-2 astrocyte differentiation requires extracellular signals, one of which is thought to be ciliary neurotrophic factor (CNTF). CNTF, however, is insufficient by itself to induce the development of stable type-2 astrocytes. In this report we show the following: (a) that molecules associated with the extracellular matrix (ECM) cooperate with CNTF to induce stable type-2 astrocyte differentiation in serumfree cultures. The combination of CNTF and the ECM-associated molecules thus mimics the effect of FCS, which has been shown previously to induce stable type-2 astrocyte differentiation in vitro. (b) Both the ECM-associated molecules and CNTF act directly on 0-2A progenitor cells and can induce them to differentiate prematurely into type-2 astrocytes. (c) ECM-associated molecules also inhibit oligodendrocyte differentiation, even in the absence of CNTF, but this inhibition is not sufficient on its own to induce type-2 astrocyte differentiation. (d) Whereas the effect of ECM on oligodendrocyte differentiation is mimicked by basic fibroblast growth factor (bFGF), the effect of ECM on type-2 astrocyte differentiation is not. (e) The ECM-associated molecules that are responsible for inhibitin~ oligodendrocyte differentiation and for cooperating with CNTF to induce type-2 astrocyte differentiation are made by non-glial cells in vitro. (f) Molecules that have these activities and bind to ECM are present in the optic nerve at the time type-2 astrocytes are thought to be developing. Y1 - 1990 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-42602 ER - TY - JOUR A1 - Sendtner, Michael A1 - Gnahn, H. A1 - Wakade, A. A1 - Thoenen, Hans T1 - Is activation of the Na\(^+\)K\(^+\) pump necessary for NGF-mediated neuronal survival? N2 - The ability of nerve growth factor to cause rapid activation of the Na+K+ pump of its responsive cells was examined by measuring the uptake of 86Rb+. A significant increase in 86Rb+ uptake in Ea chick dorsal root ganglion sensory neurons after NGF treatment was seen only if the cells had been damaged during the preparation procedure. Such damaged cells could not survive in culture in the presence of NGF, and undamaged cells that did survive in response to NGF exhibited no increased 86Rb+ uptake rate. Furthermore, cultured calf adrenal medullary cells did not show an increase in 86Rb+ uptake after treatment with NGF, although these cells respond to NGF with an increased synthesis of catecholaminergic enzymes. These results are incompatible with the hypothesis that the mechanism of action of NGF that promotes neuronal survival and enzyme induction results from an initial stimulation of the Na+K+ pump. Y1 - 1988 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-42610 ER - TY - JOUR A1 - Kaupmann, Klemens A1 - Sendtner, Michael A1 - Stöckli, Kurt A. A1 - Jockusch, Harald T1 - The gene of ciliary neurotrophic factor (cntf) maps to murine chromosome 19 and its expression is not affected in the hereditary motoneuron disease 'wobbler' of the mouse N2 - The cDNA for ciliary neurotrophic factor (CNTF), a polypeptide involved in the survival of motoneurons in mammals, has recently been cloned (Stöckli et al., Nature, 342, 920 - 923, 1989; Lin et al. Science, 246, 1023 - 1025, 1989). We have now localized the corresponding gene Cntf to chromosome 19 in the mouse, using an interspecific cross between Mus spretus and Mus musculus domesticus. The latter was carrying the gene wobbler (wr) for spinal muscular atrophy. DNA was prepared from backcross individuals and typed for the segregation of species-specific Cntf restriction fragments in relation to DNA markers of known chromosomal location. The M.spretus allele of Cntf cosegregated with chromosome 19 markers and mapped closely to Ly-1, to a region of mouse chromosome 19 with conserved synteny to human chromosome 11q. Cntf is not linked to wr, and the expression of CNTF mRNA and protein appears close to normal in facial and sciatic nerves, of affected (wr/wr) mice, suggesting that motoneuron degeneration of wobbler mice has its origin in defects other than reduced CNTF expression. KW - Mus spretus KW - interspeific backcross KW - spinal muscular atrophy KW - linkage KW - restriction fragment length polymorphism Y1 - 1991 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-42626 ER - TY - JOUR A1 - Barres, B. A. A1 - Schmid, R. A1 - Sendtner, Michael A1 - Raff, Martin C. T1 - Multiple extracellular signals are required for long-term oligodendrocyte survival N2 - We showed previously that oligodendrocytes and their precursors require continuous signalling by protein trophic factors to avoid programmed cell death in culture. Here we show that three classes of such trophic factors promote oligodendrocyte survival in vitro: (1) insulin and insulin-like growth factors (IGFs), (2) neurotrophins, particularly neurotrophin-3 (NT -3), and (3) ciliary-neurotrophic factor (CNTF), leukemia inhibitory factor (LIF) and interleukin 6 (IL-6). A single factor, or combinations of factors within the same class, promote only short-term survival of oligodendrocytes and their precursors, while combinations of factors from different classes promote survival additively. Long-term survival of oligodendrocytes in vitro requires at least one factor from each class, suggesting that multiple signals may be required for long-term oligodendrocyte survival in vivo. We also show that CNTF promotes oligodendrocyte survival in vivo, that platelet-derived growth factor (PDGF) can promote the survival of oligodendrocyte precursors in vitro by acting on a novel, very high affinity PDGF receptor, and that, in addition to its effect on survival, NT-3 is a potent mitogen for oligodendrocyte precursor cells. KW - neurotrophins KW - programmed cell death KW - apoptosis KW - ciliary-neurotrophic factor KW - interleukin 6 KW - insulin KW - insulin-likegrowth factor I Y1 - 1993 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-42644 ER - TY - JOUR A1 - Dittrich, Falk A1 - Thoenen, Hans A1 - Sendtner, Michael T1 - Ciliary neurotrophic factor: pharmacokinetics and acute-phase response in rat N2 - No abstract available Y1 - 1994 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-42639 ER - TY - RPRT A1 - Lütticken, Claudia A1 - Wegenka, Ursula M. A1 - Yuan, Juping A1 - Buschmann, Jan A1 - Schindler, Chris A1 - Ziemiecki, Andrew A1 - Harpur, Alisa G. A1 - Wilks, Andrew F. A1 - Yasukawa, Kiyoshi A1 - Taga, Tetsuya A1 - Kishimoto, Tadamitsu A1 - Barbieri, Giovanna A1 - Sendtner, Michael A1 - Pellegrini, Sandra A1 - Heinrich, Peter C. A1 - Horn, Friedemann T1 - Association of transcription factor APRF and protein kinase JAK1 with the IL-6 signal transducer gp130 N2 - Interleukin-6, leukemia inhibitory factor, oncostatin M. Interleukin-11, and cilialy neurotrophic factor bind to receptor complexes that share the signal transducer gp130. Upon binding, the ligands rapidly activate DNA binding of acute-phase response factor (APRF), a protein antigenicaly relaled to the p91 subunit of the interferon-stimulated gene factor-(ISGF-3a). These cytokines caused tyrosine phosphorylation of APRF and ISGF-3a p91. Protein kinases of the Jak family were also rapidly tyrosine phosphorylated, and both APRF and Jak1 associated with gp130. These data indicate that Jak family protein kinases may participate in IL-6 signaling and that APRF may be activated in a complex with gp130. Y1 - 1994 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-42577 ER - TY - JOUR A1 - Dohrmann, Ulrike A1 - Edgar, David A1 - Sendtner, Michael A1 - Thoenen, Hans T1 - Muscle-derived factors that support survival and promote fiber outgrowth from embryonic chick spinal motor neurons in culture N2 - The purpose of the experiments reported is to provide an unambiguous demonstration that embryonie skeletal muscle contains factors that act directly on embryonie spinal motor neurons both to support their survival and to stimulate the outgrowth of neurites. Cells of lumbar and brachial ventral spinal cords from 6-day-old chick embryos were separated by centrifugation in a two-step metrizamide gradient, and a motor neuron enriched fraction was obtained. Motor neurons were identified by retrogradely labeling with rhodamine isothiocyanate, and were enriched fourfold in the motor neuron fraction relative to unfractionated cells. In culture, the isolated motor neurons died within 3-4 days unless they were supplemented with embryonie chick skeletal muscle extract. Two functionally distinct entities separable by ammonium sulfate precipitation were responsible for the effects of muscle extracts on motor neurons. The 0-25% ammonium sulfate precipitate contained molecules that alone bad no effect on neuronal survival but when bound to polyornithine-coated culture substrata, stimulated neurite outgrowth and potentiated the survival activity present in muscle. Most of this activity was due to a laminin-like molecule being immunoprecipitated with antisera against laminin, and immunoblotting demonstrated the presence of both the A and B chains of laminin. A long-term survival activity resided in the 25-70% ammonium sulfate fraction, and its apparent total and specific activities were strongly dependent on the culture substrate. In contrast to the motor neurons, the cells from the other metrizamide fraction (including neuronal cells) could be kept in culture for a prolonged time without addition of exogenous factor(s). KW - Nervenzelle Y1 - 1986 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-72862 ER - TY - JOUR A1 - Deng, Chunchu A1 - Reinhard, Sebastian A1 - Hennlein, Luisa A1 - Eilts, Janna A1 - Sachs, Stefan A1 - Doose, Sören A1 - Jablonka, Sibylle A1 - Sauer, Markus A1 - Moradi, Mehri A1 - Sendtner, Michael T1 - Impaired dynamic interaction of axonal endoplasmic reticulum and ribosomes contributes to defective stimulus-response in spinal muscular atrophy JF - Translational Neurodegeneration N2 - Background: Axonal degeneration and defects in neuromuscular neurotransmission represent a pathological hallmark in spinal muscular atrophy (SMA) and other forms of motoneuron disease. These pathological changes do not only base on altered axonal and presynaptic architecture, but also on alterations in dynamic movements of organelles and subcellular structures that are not necessarily reflected by static histopathological changes. The dynamic interplay between the axonal endoplasmic reticulum (ER) and ribosomes is essential for stimulus-induced local translation in motor axons and presynaptic terminals. However, it remains enigmatic whether the ER and ribosome crosstalk is impaired in the presynaptic compartment of motoneurons with Smn (survival of motor neuron) deficiency that could contribute to axonopathy and presynaptic dysfunction in SMA. Methods: Using super-resolution microscopy, proximity ligation assay (PLA) and live imaging of cultured motoneurons from a mouse model of SMA, we investigated the dynamics of the axonal ER and ribosome distribution and activation. Results: We observed that the dynamic remodeling of ER was impaired in axon terminals of Smn-deficient motoneurons. In addition, in axon terminals of Smn-deficient motoneurons, ribosomes failed to respond to the brain-derived neurotrophic factor stimulation, and did not undergo rapid association with the axonal ER in response to extracellular stimuli. Conclusions: These findings implicate impaired dynamic interplay between the ribosomes and ER in axon terminals of motoneurons as a contributor to the pathophysiology of SMA and possibly also other motoneuron diseases. KW - spinal muscular atrophy KW - BDNF stimulation KW - dynamics of ribosomal assembly KW - presynaptic ER dynamics Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300649 SN - 2047-9158 VL - 11 IS - 1 ER - TY - JOUR A1 - Simon, Christian M. A1 - Rauskolb, Stefanie A1 - Gunnersen, Jennifer M. A1 - Holtmann, Bettina A1 - Drepper, Carsten A1 - Dombert, Benjamin A1 - Braga, Massimiliano A1 - Wiese, Stefan A1 - Jablonka, Sibylle A1 - Pühringer, Dirk A1 - Zielasek, Jürgen A1 - Hoeflich, Andreas A1 - Silani, Vincenzo A1 - Wolf, Eckhard A1 - Kneitz, Susanne A1 - Sommer, Claudia A1 - Toyka, Klaus V. A1 - Sendtner, Michael T1 - Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy JF - Acta Neuropathologica N2 - Diabetic neuropathy (DNP), afflicting sensory and motor nerve fibers, is a major complication in diabetes.The underlying cellular mechanisms of axon degeneration are poorly understood. IGFBP5, an inhibitory binding protein for insulin-like growth factor 1 (IGF1) is highly up-regulated in nerve biopsies of patients with DNP. We investigated the pathogenic relevance of this finding in transgenic mice overexpressing IGFBP5 in motor axons and sensory nerve fibers. These mice develop motor axonopathy and sensory deficits similar to those seen in DNP. Motor axon degeneration was also observed in mice in which the IGF1 receptor(IGF1R) was conditionally depleted in motoneurons, indicating that reduced activity of IGF1 on IGF1R in motoneurons is responsible for the observed effect. These data provide evidence that elevated expression of IGFBP5 in diabetic nerves reduces the availability of IGF1 for IGF1R on motor axons, thus leading to progressive neurodegeneration. Inhibition of IGFBP5 could thus offer novel treatment strategies for DNP. KW - Motor nerve biopsy KW - Diabetic polyneuropathy KW - Neuropathy KW - Neurotrophic factors KW - Axonal degeneration Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-154569 VL - 130 SP - 373 EP - 387 ER - TY - JOUR A1 - Maass, Anne A1 - Düzel, Sandra A1 - Brigadski, Tanja A1 - Goerke, Monique A1 - Becke, Andreas A1 - Sobieray, Uwe A1 - Neumann, Katja A1 - Lövdén, Martin A1 - Lindenberger, Ulman A1 - Bäckman, Lars A1 - Braun-Dullaeus, Rüdiger A1 - Ahrens, Dörte A1 - Heinze, Hans-Jochen A1 - Müller, Notger G. A1 - Lessmann, Volkmar A1 - Sendtner, Michael A1 - Düzel, Emrah T1 - Relationships of peripheral IGF-1, VEGF and BDNF levels to exercise-related changes in memory, hippocampal perfusion and volumes in older adults JF - NeuroImage N2 - Animal models point towards a key role of brain-derived neurotrophic factor (BDNF), insulin-like growth factor-I (IGF-I) and vascular endothelial growth factor (VEGF) in mediating exercise-induced structural and functional changes in the hippocampus. Recently, also platelet derived growth factor-C (PDGF-C) has been shown to promote blood vessel growth and neuronal survival. Moreover, reductions of these neurotrophic and angiogenic factors in old age have been related to hippocampal atrophy, decreased vascularization and cognitive decline. In a 3-month aerobic exercise study, forty healthy older humans (60 to 77 years) were pseudo-randomly assigned to either an aerobic exercise group (indoor treadmill, n = 21) or to a control group (indoor progressive-muscle relaxation/stretching, n = 19). As reported recently, we found evidence for fitness-related perfusion changes of the aged human hippocampus that were closely linked to changes in episodic memory function. Here, we test whether peripheral levels of BDNF, IGF-I, VEGF or PDGF-C are related to changes in hippocampal blood flow, volume and memory performance. Growth factor levels were not significantly affected by exercise, and their changes were not related to changes in fitness or perfusion. However, changes in IGF-I levels were positively correlated with hippocampal volume changes (derived by manual volumetry and voxel-based morphometry) and late verbal recall performance, a relationship that seemed to be independent of fitness, perfusion or their changes over time. These preliminary findings link IGF-I levels to hippocampal volume changes and putatively hippocampus-dependent memory changes that seem to occur over time independently of exercise. We discuss methodological shortcomings of our study and potential differences in the temporal dynamics of how IGF-1, VEGF and BDNF may be affected by exercise and to what extent these differences may have led to the negative findings reported here. KW - Exercise KW - Neurotrophic factors KW - Hippocampus KW - Vascular plasticity KW - Aging Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-189219 VL - 131 ER - TY - JOUR A1 - Düzel, Emrah A1 - van Praag, Henriette A1 - Sendtner, Michael T1 - Can physical exercise in old age improve memory and hippocampal function? JF - Brain N2 - Physical exercise can convey a protective effect against cognitive decline in ageing and Alzheimer’s disease. While the long-term health-promoting and protective effects of exercise are encouraging, it’s potential to induce neuronal and vascular plasticity in the ageing brain is still poorly understood. It remains unclear whether exercise slows the trajectory of normal ageing by modifying vascular and metabolic risk factors and/or consistently boosts brain function by inducing structural and neurochemical changes in the hippocampus and related medial temporal lobe circuitry—brain areas that are important for learning and memory. Hence, it remains to be established to what extent exercise interventions in old age can improve brain plasticity above and beyond preservation of function. Existing data suggest that exercise trials aiming for improvement and preservation may require different outcome measures and that the balance between the two may depend on exercise intensity and duration, the presence of preclinical Alzheimer’s disease pathology, vascular and metabolic risk factors and genetic variability. KW - hippocampus KW - exercise KW - cerebral blood flow KW - Alzheimer's disease KW - memory Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-190721 VL - 139 IS - 3 ER - TY - JOUR A1 - Lüningschrör, Patrick A1 - Binotti, Beyenech A1 - Dombert, Benjamin A1 - Heimann, Peter A1 - Perez-Lara, Angel A1 - Slotta, Carsten A1 - Thau-Habermann, Nadine A1 - von Collenberg, Cora R. A1 - Karl, Franziska A1 - Damme, Markus A1 - Horowitz, Arie A1 - Maystadt, Isabelle A1 - Füchtbauer, Annette A1 - Füchtbauer, Ernst-Martin A1 - Jablonka, Sibylle A1 - Blum, Robert A1 - Üçeyler, Nurcan A1 - Petri, Susanne A1 - Kaltschmidt, Barbara A1 - Jahn, Reinhard A1 - Kaltschmidt, Christian A1 - Sendtner, Michael T1 - Plekhg5-regulated autophagy of synaptic vesicles reveals a pathogenic mechanism in motoneuron disease JF - Nature Communications N2 - Autophagy-mediated degradation of synaptic components maintains synaptic homeostasis but also constitutes a mechanism of neurodegeneration. It is unclear how autophagy of synaptic vesicles and components of presynaptic active zones is regulated. Here, we show that Pleckstrin homology containing family member 5 (Plekhg5) modulates autophagy of synaptic vesicles in axon terminals of motoneurons via its function as a guanine exchange factor for Rab26, a small GTPase that specifically directs synaptic vesicles to preautophagosomal structures. Plekhg5 gene inactivation in mice results in a late-onset motoneuron disease, characterized by degeneration of axon terminals. Plekhg5-depleted cultured motoneurons show defective axon growth and impaired autophagy of synaptic vesicles, which can be rescued by constitutively active Rab26. These findings define a mechanism for regulating autophagy in neurons that specifically targets synaptic vesicles. Disruption of this mechanism may contribute to the pathophysiology of several forms of motoneuron disease. KW - autophagy KW - synaptic vesicles KW - Pleckstrin homology containing family member 5 (Plekhg5) KW - regulation KW - motoneuron disease Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170048 VL - 8 IS - 678 ER - TY - JOUR A1 - von Collenberg, Cora R. A1 - Schmitt, Dominique A1 - Rülicke, Thomas A1 - Sendtner, Michael A1 - Blum, Robert A1 - Buchner, Erich T1 - An essential role of the mouse synapse-associated protein Syap1 in circuits for spontaneous motor activity and rotarod balance JF - Biology Open N2 - Synapse-associated protein 1 (Syap1) is the mammalian homologue of synapse-associated protein of 47 kDa (Sap47) in Drosophila. Genetic deletion of Sap47 leads to deficiencies in short-term plasticity and associative memory processing in flies. In mice, Syap1 is prominently expressed in the nervous system, but its function is still unclear. We have generated Syap1 knockout mice and tested motor behaviour and memory. These mice are viable and fertile but display distinct deficiencies in motor behaviour. Locomotor activity specifically appears to be reduced in early phases when voluntary movement is initiated. On the rotarod, a more demanding motor test involving control by sensory feedback, Syap1-deficient mice dramatically fail to adapt to accelerated speed or to a change in rotation direction. Syap1 is highly expressed in cerebellar Purkinje cells and cerebellar nuclei. Thus, this distinct motor phenotype could be due to a so-far unknown function of Syap1 in cerebellar sensorimotor control. The observed motor defects are highly specific since other tests in the modified SHIRPA exam, as well as cognitive tasks like novel object recognition, Pavlovian fear conditioning, anxiety-like behaviour in open field dark-light transition and elevated plus maze do not appear to be affected in Syap1 knockout mice. KW - Syap1 knockout KW - Motor behaviour KW - Associative learning KW - Fear conditioning KW - Object recognition Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201986 N1 - PDF includes: Correction: An essential role of the mouse synapse-associated protein Syap1 in circuits for spontaneous motor activity and rotarod balance - February 15, 2020. Biology Open (2020) 9, bio048942. doi:10.1242/bio.048942 VL - 8 ER - TY - JOUR A1 - Andreska, Thomas A1 - Lüningschrör, Patrick A1 - Sendtner, Michael T1 - Regulation of TrkB cell surface expression — a mechanism for modulation of neuronal responsiveness to brain-derived neurotrophic factor JF - Cell and Tissue Research N2 - Neurotrophin signaling via receptor tyrosine kinases is essential for the development and function of the nervous system in vertebrates. TrkB activation and signaling show substantial differences to other receptor tyrosine kinases of the Trk family that mediate the responses to nerve growth factor and neurotrophin-3. Growing evidence suggests that TrkB cell surface expression is highly regulated and determines the sensitivity of neurons to brain-derived neurotrophic factor (BDNF). This translocation of TrkB depends on co-factors and modulators of cAMP levels, N-glycosylation, and receptor transactivation. This process can occur in very short time periods and the resulting rapid modulation of target cell sensitivity to BDNF could represent a mechanism for fine-tuning of synaptic plasticity and communication in complex neuronal networks. This review focuses on those modulatory mechanisms in neurons that regulate responsiveness to BDNF via control of TrkB surface expression. KW - BDNF KW - TrkB KW - subcellular trafficking KW - transactivation KW - synaptic plasticity Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235055 VL - 382 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 - TY - JOUR A1 - Haberstumpf, Sophia A1 - Forster, André A1 - Leinweber, Jonas A1 - Rauskolb, Stefanie A1 - Hewig, Johannes A1 - Sendtner, Michael A1 - Lauer, Martin A1 - Polak, Thomas A1 - Deckert, Jürgen A1 - Herrmann, Martin J. T1 - Measurement invariance testing of longitudinal neuropsychiatric test scores distinguishes pathological from normative cognitive decline and highlights its potential in early detection research JF - Journal of Neuropsychology N2 - Objective Alzheimer’s disease (AD) is a growing challenge worldwide, which is why the search for early-onset predictors must be focused as soon as possible. Longitudinal studies that investigate courses of neuropsychological and other variables screen for such predictors correlated to mild cognitive impairment (MCI). However, one often neglected issue in analyses of such studies is measurement invariance (MI), which is often assumed but not tested for. This study uses the absence of MI (non-MI) and latent factor scores instead of composite variables to assess properties of cognitive domains, compensation mechanisms, and their predictability to establish a method for a more comprehensive understanding of pathological cognitive decline. Methods An exploratory factor analysis (EFA) and a set of increasingly restricted confirmatory factor analyses (CFAs) were conducted to find latent factors, compared them with the composite approach, and to test for longitudinal (partial-)MI in a neuropsychiatric test battery, consisting of 14 test variables. A total of 330 elderly (mean age: 73.78 ± 1.52 years at baseline) were analyzed two times (3 years apart). Results EFA revealed a four-factor model representing declarative memory, attention, working memory, and visual–spatial processing. Based on CFA, an accurate model was estimated across both measurement timepoints. Partial non-MI was found for parameters such as loadings, test- and latent factor intercepts as well as latent factor variances. The latent factor approach was preferable to the composite approach. Conclusion The overall assessment of non-MI latent factors may pose a possible target for this field of research. Hence, the non-MI of variances indicated variables that are especially suited for the prediction of pathological cognitive decline, while non-MI of intercepts indicated general aging-related decline. As a result, the sole assessment of MI may help distinguish pathological from normative aging processes and additionally may reveal compensatory neuropsychological mechanisms. KW - Alzheimer’s disease KW - early-onset predictors KW - mild cognitive impairment Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-318932 VL - 16 IS - 2 SP - 324 EP - 352 ER - TY - JOUR A1 - Franco-Espin, Julio A1 - Gatius, Alaó A1 - Armengol, José Ángel A1 - Arumugam, Saravanan A1 - Moradi, Mehri A1 - Sendtner, Michael A1 - Calderó, Jordi A1 - Tabares, Lucia T1 - SMN is physiologically downregulated at wild-type motor nerve terminals but aggregates together with neurofilaments in SMA mouse models JF - Biomolecules N2 - Survival motor neuron (SMN) is an essential and ubiquitously expressed protein that participates in several aspects of RNA metabolism. SMN deficiency causes a devastating motor neuron disease called spinal muscular atrophy (SMA). SMN forms the core of a protein complex localized at the cytoplasm and nuclear gems and that catalyzes spliceosomal snRNP particle synthesis. In cultured motor neurons, SMN is also present in dendrites and axons, and forms part of the ribonucleoprotein transport granules implicated in mRNA trafficking and local translation. Nevertheless, the distribution, regulation, and role of SMN at the axons and presynaptic motor terminals in vivo are still unclear. By using conventional confocal microscopy and STED super-resolution nanoscopy, we found that SMN appears in the form of granules distributed along motor axons at nerve terminals. Our fluorescence in situ hybridization and electron microscopy studies also confirmed the presence of β-actin mRNA, ribosomes, and polysomes in the presynaptic motor terminal, key elements of the protein synthesis machinery involved in local translation in this compartment. SMN granules co-localize with the microtubule-associated protein 1B (MAP1B) and neurofilaments, suggesting that the cytoskeleton participates in transporting and positioning the granules. We also found that, while SMN granules are physiologically downregulated at the presynaptic element during the period of postnatal maturation in wild-type (non-transgenic) mice, they accumulate in areas of neurofilament aggregation in SMA mice, suggesting that the high expression of SMN at the NMJ, together with the cytoskeletal defects, contribute to impairing the bi-directional traffic of proteins and organelles between the axon and the presynaptic terminal. KW - spinal muscular atrophy KW - motor neuron degeneration KW - SMN granules KW - neuromuscular junction KW - β-actin mRNA KW - MAP1B KW - neurofilaments Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290263 SN - 2218-273X VL - 12 IS - 10 ER - TY - JOUR A1 - Massih, Bita A1 - Veh, Alexander A1 - Schenke, Maren A1 - Mungwa, Simon A1 - Seeger, Bettina A1 - Selvaraj, Bhuvaneish T. A1 - Chandran, Siddharthan A1 - Reinhardt, Peter A1 - Sterneckert, Jared A1 - Hermann, Andreas A1 - Sendtner, Michael A1 - Lüningschrör, Patrick T1 - A 3D cell culture system for bioengineering human neuromuscular junctions to model ALS JF - Frontiers in Cell and Developmental Biology N2 - 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. KW - NMJ–neuromuscular junction KW - motoneuron (MN) KW - skeletal muscle KW - iPSC (induced pluripotent stem cells) KW - 3D cell culture Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304161 SN - 2296-634X VL - 11 ER -