Dokument-ID Dokumenttyp Verfasser/Autoren Herausgeber Haupttitel Abstract Auflage Verlagsort Verlag Erscheinungsjahr Seitenzahl Schriftenreihe Titel Schriftenreihe Bandzahl ISBN Quelle der Hochschulschrift Konferenzname Quelle:Titel Quelle:Jahrgang Quelle:Heftnummer Quelle:Erste Seite Quelle:Letzte Seite URN DOI Abteilungen OPUS4-29026 Wissenschaftlicher Artikel Franco-Espin, Julio; Gatius, Alaó; Armengol, José Ángel; Arumugam, Saravanan; Moradi, Mehri; Sendtner, Michael; Calderó, Jordi; Tabares, Lucia SMN is physiologically downregulated at wild-type motor nerve terminals but aggregates together with neurofilaments in SMA mouse models 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. 2022 Biomolecules 12 10 urn:nbn:de:bvb:20-opus-290263 10.3390/biom12101524 Institut für Klinische Neurobiologie OPUS4-31893 Wissenschaftlicher Artikel Haberstumpf, Sophia; Forster, André; Leinweber, Jonas; Rauskolb, Stefanie; Hewig, Johannes; Sendtner, Michael; Lauer, Martin; Polak, Thomas; Deckert, Jürgen; Herrmann, Martin J. Measurement invariance testing of longitudinal neuropsychiatric test scores distinguishes pathological from normative cognitive decline and highlights its potential in early detection research 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. 2022 28 Journal of Neuropsychology 16 2 324 352 urn:nbn:de:bvb:20-opus-318932 10.1111/jnp.12269 Institut für Klinische Neurobiologie OPUS4-30064 Wissenschaftlicher Artikel Deng, Chunchu; Reinhard, Sebastian; Hennlein, Luisa; Eilts, Janna; Sachs, Stefan; Doose, Sören; Jablonka, Sibylle; Sauer, Markus; Moradi, Mehri; Sendtner, Michael Impaired dynamic interaction of axonal endoplasmic reticulum and ribosomes contributes to defective stimulus-response in spinal muscular atrophy 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. 2022 Translational Neurodegeneration 11 1 urn:nbn:de:bvb:20-opus-300649 10.1186/s40035-022-00304-2 Institut für Klinische Neurobiologie OPUS4-26568 Wissenschaftlicher Artikel Ghanawi, Hanaa; Hennlein, Luisa; Zare, Abdolhossein; Bader, Jakob; Salehi, Saeede; Hornburg, Daniel; Ji, Changhe; Sivadasan, Rajeeve; Drepper, Carsten; Meissner, Felix; Mann, Matthias; Jablonka, Sibylle; Briese, Michael; Sendtner, Michael Loss of full-length hnRNP R isoform impairs DNA damage response in motoneurons by inhibiting Yb1 recruitment to chromatin Neurons critically rely on the functions of RNA-binding proteins to maintain their polarity and resistance to neurotoxic stress. HnRNP R has a diverse range of post-transcriptional regulatory functions and is important for neuronal development by regulating axon growth. Hnrnpr pre-mRNA undergoes alternative splicing giving rise to a full-length protein and a shorter isoform lacking its N-terminal acidic domain. To investigate functions selectively associated with the full-length hnRNP R isoform, we generated a Hnrnpr knockout mouse (Hnrnpr\(^{tm1a/tm1a}\)) in which expression of full-length hnRNP R was abolished while production of the truncated hnRNP R isoform was retained. Motoneurons cultured from Hnrnpr\(^{tm1a/tm1a}\) mice did not show any axonal growth defects but exhibited enhanced accumulation of double-strand breaks and an impaired DNA damage response upon exposure to genotoxic agents. Proteomic analysis of the hnRNP R interactome revealed the multifunctional protein Yb1 as a top interactor. Yb1-depleted motoneurons were defective in DNA damage repair. We show that Yb1 is recruited to chromatin upon DNA damage where it interacts with gamma-H2AX, a mechanism that is dependent on full-length hnRNP R. Our findings thus suggest a novel role of hnRNP R in maintaining genomic integrity and highlight the function of its N-terminal acidic domain in this context. 2021 12284-12305 Nucleic Acids Research 49 21 urn:nbn:de:bvb:20-opus-265687 10.1093/nar/gkab1120 Institut für Klinische Neurobiologie OPUS4-25912 Wissenschaftlicher Artikel Ji, Changhe; Bader, Jakob; Ramanathan, Pradhipa; Hennlein, Luisa; Meissner, Felix; Jablonka, Sibylle; Mann, Matthias; Fischer, Utz; Sendtner, Michael; Briese, Michael Interaction of 7SK with the Smn complex modulates snRNP production Gene expression requires tight coordination of the molecular machineries that mediate transcription and splicing. While the interplay between transcription kinetics and spliceosome fidelity has been investigated before, less is known about mechanisms regulating the assembly of the spliceosomal machinery in response to transcription changes. Here, we report an association of the Smn complex, which mediates spliceosomal snRNP biogenesis, with the 7SK complex involved in transcriptional regulation. We found that Smn interacts with the 7SK core components Larp7 and Mepce and specifically associates with 7SK subcomplexes containing hnRNP R. The association between Smn and 7SK complexes is enhanced upon transcriptional inhibition leading to reduced production of snRNPs. Taken together, our findings reveal a functional association of Smn and 7SK complexes that is governed by global changes in transcription. Thus, in addition to its canonical nuclear role in transcriptional regulation, 7SK has cytosolic functions in fine-tuning spliceosome production according to transcriptional demand. 2021 1278 Nature Communications 12 1 urn:nbn:de:bvb:20-opus-259125 10.1038/s41467-021-21529-1 Institut für Klinische Neurobiologie OPUS4-25661 Wissenschaftlicher Artikel Briese, Michael; Sendtner, Michael Keeping the balance: the noncoding RNA 7SK as a master regulator for neuron development and function The noncoding RNA 7SK is a critical regulator of transcription by adjusting the activity of the kinase complex P-TEFb. Release of P-TEFb from 7SK stimulates transcription at many genes by promoting productive elongation. Conversely, P-TEFb sequestration by 7SK inhibits transcription. Recent studies have shown that 7SK functions are particularly important for neuron development and maintenance and it can thus be hypothesized that 7SK is at the center of many signaling pathways contributing to neuron function. 7SK activates neuronal gene expression programs that are key for terminal differentiation of neurons. Proteomics studies revealed a complex protein interactome of 7SK that includes several RNA-binding proteins. Some of these novel 7SK subcomplexes exert non-canonical cytosolic functions in neurons by regulating axonal mRNA transport and fine-tuning spliceosome production in response to transcription alterations. Thus, a picture emerges according to which 7SK acts as a multi-functional RNA scaffold that is integral for neuron homeostasis. 2021 BioEssays 43 8 urn:nbn:de:bvb:20-opus-256613 10.1002/bies.202100092 Institut für Klinische Neurobiologie OPUS4-23505 Wissenschaftlicher Artikel Andreska, Thomas; Lüningschrör, Patrick; Sendtner, Michael Regulation of TrkB cell surface expression — a mechanism for modulation of neuronal responsiveness to brain-derived neurotrophic factor 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. 2020 5-14 Cell and Tissue Research 382 urn:nbn:de:bvb:20-opus-235055 10.1007/s00441-020-03224-7 Institut für Klinische Neurobiologie OPUS4-23066 Wissenschaftlicher Artikel Markert, Sebastian M.; Skoruppa, Michael; Yu, Bin; Mulcahy, Ben; Zhen, Mai; Gao, Shangbang; Sendtner, Michael; Stigloher, Christian Overexpression of an ALS-associated FUS mutation in C. elegans disrupts NMJ morphology and leads to defective neuromuscular transmission The amyotrophic lateral sclerosis (ALS) neurodegenerative disorder has been associated with multiple genetic lesions, including mutations in the gene for fused in sarcoma (FUS), a nuclear-localized RNA/DNA-binding protein. Neuronal expression of the pathological form of FUS proteins in Caenorhabditis elegans results in mislocalization and aggregation of FUS in the cytoplasm, and leads to impairment of motility. However, the mechanisms by which the mutant FUS disrupts neuronal health and function remain unclear. Here we investigated the impact of ALS-associated FUS on motor neuron health using correlative light and electron microscopy, electron tomography, and electrophysiology. We show that ectopic expression of wild-type or ALS-associated human FUS impairs synaptic vesicle docking at neuromuscular junctions. ALS-associated FUS led to the emergence of a population of large, electron-dense, and filament-filled endosomes. Electrophysiological recording revealed reduced transmission from motor neurons to muscles. Together, these results suggest a pathological effect of ALS-causing FUS at synaptic structure and function organization. 2020 Biology Open 9 urn:nbn:de:bvb:20-opus-230662 10.1242/bio.055129 Institut für Klinische Neurobiologie OPUS4-23032 Wissenschaftlicher Artikel Briese, Michael; Saal-Bauernschubert, Lena; Lüningschrör, Patrick; Moradi, Mehri; Dombert, Benjamin; Surrey, Verena; Appenzeller, Silke; Deng, Chunchu; Jablonka, Sibylle; Sendtner, Michael Loss of Tdp-43 disrupts the axonal transcriptome of motoneurons accompanied by impaired axonal translation and mitochondria function Protein inclusions containing the RNA-binding protein TDP-43 are a pathological hallmark of amyotrophic lateral sclerosis and other neurodegenerative disorders. The loss of TDP-43 function that is associated with these inclusions affects post-transcriptional processing of RNAs in multiple ways including pre-mRNA splicing, nucleocytoplasmic transport, modulation of mRNA stability and translation. In contrast, less is known about the role of TDP-43 in axonal RNA metabolism in motoneurons. Here we show that depletion of Tdp-43 in primary motoneurons affects axon growth. This defect is accompanied by subcellular transcriptome alterations in the axonal and somatodendritic compartment. The axonal localization of transcripts encoding components of the cytoskeleton, the translational machinery and transcripts involved in mitochondrial energy metabolism were particularly affected by loss of Tdp-43. Accordingly, we observed reduced protein synthesis and disturbed mitochondrial functions in axons of Tdp-43-depleted motoneurons. Treatment with nicotinamide rescued the axon growth defect associated with loss of Tdp-43. These results show that Tdp-43 depletion in motoneurons affects several pathways integral to axon health indicating that loss of TDP-43 function could thus make a major contribution to axonal pathomechanisms in ALS. 2020 Acta Neuropathologica Communications 8 urn:nbn:de:bvb:20-opus-230322 10.1186/s40478-020-00987-6 Neurologische Klinik und Poliklinik OPUS4-20753 Wissenschaftlicher Artikel Lüningschrör, Patrick; Slotta, Carsten; Heimann, Peter; Briese, Michael; Weikert, Ulrich M.; Massih, Bita; Appenzeller, Silke; Sendtner, Michael; Kaltschmidt, Christian; Kaltschmidt, Barbara Absence of Plekhg5 Results in Myelin Infoldings Corresponding to an Impaired Schwann Cell Autophagy, and a Reduced T-Cell Infiltration Into Peripheral Nerves Inflammation and dysregulation of the immune system are hallmarks of several neurodegenerative diseases. An activated immune response is considered to be the cause of myelin breakdown in demyelinating disorders. In the peripheral nervous system (PNS), myelin can be degraded in an autophagy-dependent manner directly by Schwann cells or by macrophages, which are modulated by T-lymphocytes. Here, we show that the NF-κB activator Pleckstrin homology containing family member 5 (Plekhg5) is involved in the regulation of both Schwann cell autophagy and recruitment of T-lymphocytes in peripheral nerves during motoneuron disease. Plekhg5-deficient mice show defective axon/Schwann cell units characterized by myelin infoldings in peripheral nerves. Even at late stages, Plekhg5-deficient mice do not show any signs of demyelination and inflammation. Using RNAseq, we identified a transcriptional signature for an impaired immune response in sciatic nerves, which manifested in a reduced number of CD4\(^+\) and CD8\(^+\) T-cells. These findings identify Plekhg5 as a promising target to impede myelin breakdown in demyelinating PNS disorders. 2020 Frontiers in Cellular Neuroscience 14 urn:nbn:de:bvb:20-opus-207538 10.3389/fncel.2020.00185 Institut für Klinische Neurobiologie OPUS4-19072 Wissenschaftlicher Artikel Düzel, Emrah; van Praag, Henriette; Sendtner, Michael Can physical exercise in old age improve memory and hippocampal function? 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. 2016 662-673 Brain 139 3 urn:nbn:de:bvb:20-opus-190721 10.1093/brain/awv407 Institut für Klinische Neurobiologie OPUS4-18921 Wissenschaftlicher Artikel Maass, Anne; Düzel, Sandra; Brigadski, Tanja; Goerke, Monique; Becke, Andreas; Sobieray, Uwe; Neumann, Katja; Lövdén, Martin; Lindenberger, Ulman; Bäckman, Lars; Braun-Dullaeus, Rüdiger; Ahrens, Dörte; Heinze, Hans-Jochen; Müller, Notger G.; Lessmann, Volkmar; Sendtner, Michael; Düzel, Emrah Relationships of peripheral IGF-1, VEGF and BDNF levels to exercise-related changes in memory, hippocampal perfusion and volumes in older adults 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. 2016 142-154 NeuroImage 131 urn:nbn:de:bvb:20-opus-189219 10.1016/j.neuroimage.2015.10.084 Institut für Klinische Neurobiologie OPUS4-18823 Wissenschaftlicher Artikel Yadav, Preeti; Selvaraj, Bhuvaneish T.; Bender, Florian L. P.; Behringer, Marcus; Moradi, Mehri; Sivadasan, Rajeeve; Dombert, Benjamin; Blum, Robert; Asan, Esther; Sauer, Markus; Julien, Jean-Pierre; Sendtner, Michael Neurofilament depletion improves microtubule dynamics via modulation of Stat3/stathmin signaling 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. 2016 93-110 Acta Neuropathologica 132 1 urn:nbn:de:bvb:20-opus-188234 10.1007/s00401-016-1564-y Institut für Klinische Neurobiologie OPUS4-18725 Wissenschaftlicher Artikel Schmitt, Dominique; Funk, Natalia; Blum, Robert; Asan, Esther; Andersen, Lill; Rülicke, Thomas; Sendtner, Michael; Buchner, Erich Initial characterization of a Syap1 knock-out mouse and distribution of Syap1 in mouse brain and cultured motoneurons Synapse-associated protein 1 (Syap1/BSTA) is the mammalian homologue of Sap47 (synapse-associated protein of 47 kDa) in Drosophila. Sap47 null mutant larvae show reduced short-term synaptic plasticity and a defect in associative behavioral plasticity. In cultured adipocytes, Syap1 functions as part of a complex that phosphorylates protein kinase B alpha/Akt1 (Akt1) at Ser\(^{473}\) and promotes differentiation. The role of Syap1 in the vertebrate nervous system is unknown. Here, we generated a Syap1 knock-out mouse and show that lack of Syap1 is compatible with viability and fertility. Adult knock-out mice show no overt defects in brain morphology. In wild-type brain, Syap1 is found widely distributed in synaptic neuropil, notably in regions rich in glutamatergic synapses, but also in perinuclear structures associated with the Golgi apparatus of specific groups of neuronal cell bodies. In cultured motoneurons, Syap1 is located in axons and growth cones and is enriched in a perinuclear region partially overlapping with Golgi markers. We studied in detail the influence of Syap1 knockdown and knockout on structure and development of these cells. Importantly, Syap1 knockout does not affect motoneuron survival or axon growth. Unexpectedly, neither knockdown nor knockout of Syap1 in cultured motoneurons is associated with reduced Ser\(^{473}\) or Thr\(^{308}\) phosphorylation of Akt. Our findings demonstrate a widespread expression of Syap1 in the mouse central nervous system with regionally specific distribution patterns as illustrated in particular for olfactory bulb, hippocampus, and cerebellum. 2016 489-512 Histochemistry and Cell Biology 146 4 urn:nbn:de:bvb:20-opus-187258 10.1007/s00418-016-1457-0 Institut für Klinische Neurobiologie OPUS4-20198 Wissenschaftlicher Artikel von Collenberg, Cora R.; Schmitt, Dominique; Rülicke, Thomas; Sendtner, Michael; Blum, Robert; Buchner, Erich An essential role of the mouse synapse-associated protein Syap1 in circuits for spontaneous motor activity and rotarod balance 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. 2019 bio042366 Biology Open 8 urn:nbn:de:bvb:20-opus-201986 10.1242/bio.042366 Institut für Klinische Neurobiologie OPUS4-17004 Wissenschaftlicher Artikel Lüningschrör, Patrick; Binotti, Beyenech; Dombert, Benjamin; Heimann, Peter; Perez-Lara, Angel; Slotta, Carsten; Thau-Habermann, Nadine; von Collenberg, Cora R.; Karl, Franziska; Damme, Markus; Horowitz, Arie; Maystadt, Isabelle; Füchtbauer, Annette; Füchtbauer, Ernst-Martin; Jablonka, Sibylle; Blum, Robert; Üçeyler, Nurcan; Petri, Susanne; Kaltschmidt, Barbara; Jahn, Reinhard; Kaltschmidt, Christian; Sendtner, Michael Plekhg5-regulated autophagy of synaptic vesicles reveals a pathogenic mechanism in motoneuron disease 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. 2017 Nature Communications 8 678 urn:nbn:de:bvb:20-opus-170048 10.1038/s41467-017-00689-z Institut für Klinische Neurobiologie OPUS4-13461 Wissenschaftlicher Artikel Gresle, Melissa M.; Alexandrou, Estella; Wu, Qizhu; Egan, Gary; Jokubaitis, Vilija; Ayers, Margaret; Jonas, Anna; Doherty, William; Friedhuber, Anna; Shaw, Gerry; Sendtner, Michael; Emery, Ben; Kilpatrick, Trevor; Butzkueven, Helmut Leukemia Inhibitory Factor Protects Axons in Experimental Autoimmune Encephalomyelitis via an Oligodendrocyte-Independent Mechanism Leukemia inhibitory factor (LIF) and Ciliary Neurotrophic factor (CNTF) are members of the interleukin-6 family of cytokines, defined by use of the gp130 molecule as an obligate receptor. In the murine experimental autoimmune encephalomyelitis (EAE) model, antagonism of LIF and genetic deletion of CNTF worsen disease. The potential mechanism of action of these cytokines in EAE is complex, as gp130 is expressed by all neural cells, and could involve immuno-modulation, reduction of oligodendrocyte injury, neuronal protection, or a combination of these actions. In this study we aim to investigate whether the beneficial effects of CNTF/LIF signalling in EAE are associated with axonal protection; and whether this requires signalling through oligodendrocytes. We induced MOG\(_{35-55}\) EAE in CNTF, LIF and double knockout mice. On a CNTF null background, LIF knockout was associated with increased EAE severity (EAE grade 2.1\(\pm\)0.14 vs 2.6\(\pm\)0.19; P<0.05). These mice also showed increased axonal damage relative to LIF heterozygous mice, as indicated by decreased optic nerve parallel diffusivity on MRI (1540\(\pm\)207 \(\mu\)m\(^2\)-/s vs 1310\(\pm\)175 \(\mu\)m\(^2\)-/s; P<0.05), and optic nerve (-12.5%) and spinal cord (-16%) axon densities; and increased serum neurofilament-H levels (2.5 fold increase). No differences in inflammatory cell numbers or peripheral auto-immune T-cell priming were evident. Oligodendrocyte-targeted gp130 knockout mice showed that disruption of CNTF/LIF signalling in these cells has no effect on acute EAE severity. These studies demonstrate that endogenous CNTF and LIF act centrally to protect axons from acute inflammatory destruction via an oligodendrocyte-independent mechanism. 2012 e47379 PLoS One 7 10 urn:nbn:de:bvb:20-opus-134617 10.1371/journal.pone.0047379 Institut für Klinische Neurobiologie OPUS4-15467 Wissenschaftlicher Artikel Thangaraj Selvaraj, Bhuvaneish; Frank, Nicolas; Bender, Florian L. P.; Asan, Esther; Sendtner, Michael Local axonal function of STAT3 rescues axon degeneration in the pmn model of motoneuron disease Axonal maintenance, plasticity, and regeneration are influenced by signals from neighboring cells, in particular Schwann cells of the peripheral nervous system. Schwann cells produce neurotrophic factors, but the mechanisms by which ciliary neurotrophic factor (CNTF) and other neurotrophic molecules modify the axonal cytoskeleton are not well understood. In this paper, we show that activated signal transducer and activator of transcription-3 (STAT3), an intracellular mediator of the effects of CNTF and other neurotrophic cytokines, acts locally in axons of motoneurons to modify the tubulin cytoskeleton. Specifically, we show that activated STAT3 interacted with stathmin and inhibited its microtubule-destabilizing activity. Thus, ectopic CNTF-mediated activation of STAT3 restored axon elongation and maintenance in motoneurons from progressive motor neuronopathy mutant mice, a mouse model of motoneuron disease. This mechanism could also be relevant for other neurodegenerative diseases and provide a target for new therapies for axonal degeneration. 2012 14 The Journal of Cell Biology 199 3 437 451 urn:nbn:de:bvb:20-opus-154675 10.1083/jcb.201203109 Institut für Anatomie und Zellbiologie OPUS4-15464 Wissenschaftlicher Artikel Majounie, Elisa; Renton, Alan E.; Mok, Kin; Dopper, Elise G. P.; Waite, Adrian; Rollinson, Sara; Chiò, Adriano; Restagno, Gabriella; Nicolaou, Nayia; Simon-Sanchez, Javier; van Swieten, John C.; Abramzon, Yevgeniya; Johnson, Janel O.; Sendtner, Michael; Pamphlett, Roger; Orrell, Richard W.; Mead, Simon; Sidle, Katie C.; Houlden, Henry; Rohrer, Jonathan D.; Morrison, Karen E.; Pall, Hardev; Talbot, Kevin; Ansorge, Olaf; Hernandez, Dena G.; Arepalli, Sampath; Sabatelli, Mario; Mora, Gabriele; Corbo, Massimo; Giannini, Fabio; Calvo, Andrea; Englund, Elisabet; Borghero, Giuseppe; Floris, Gian Luca; Remes, Anne M.; Laaksovirta, Hannu; McCluskey, Leo; Trojanowski, John Q.; Van Deerlin, Vivianna M.; Schellenberg, Gerard D.; Nalls, Michael A.; Drory, Vivian E.; Lu, Chin-Song; Yeh, Tu-Hsueh; Ishiura, Hiroyuki; Takahashi, Yuji; Tsuji, Shoji; Le Ber, Isabelle; Brice, Alexis; Drepper, Carsten; Williams, Nigel; Kirby, Janine; Shaw, Pamela; Hardy, John; Tienari, Pentti J.; Heutink, Peter; Morris, Huw R.; Pickering-Brown, Stuart; Traynor, Bryan J. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study Background We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Methods We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion. Findings In patients with sporadic ALS, we identified the repeat expansion in 236 (7·0%) of 3377 white individuals from the USA, Europe, and Australia, two (4·1%) of 49 black individuals from the USA, and six (8·3%) of 72 Hispanic individuals from the USA. The mutation was present in 217 (39·3%) of 552 white individuals with familial ALS from Europe and the USA. 59 (6·0%) of 981 white Europeans with sporadic FTD had the mutation, as did 99 (24·8%) of 400 white Europeans with familial FTD. Data for other ethnic groups were sparse, but we identified one Asian patient with familial ALS (from 20 assessed) and two with familial FTD (from three assessed) who carried the mutation. The mutation was not carried by the three Native Americans or 360 patients from Asia or the Pacific Islands with sporadic ALS who were tested, or by 41 Asian patients with sporadic FTD. All patients with the repeat expansion had (partly or fully) the founder haplotype, suggesting a one-off expansion occurring about 1500 years ago. The pathogenic expansion was non-penetrant in individuals younger than 35 years, 50% penetrant by 58 years, and almost fully penetrant by 80 years. Interpretation A common Mendelian genetic lesion in C9orf72 is implicated in many cases of sporadic and familial ALS and FTD. Testing for this pathogenic expansion should be considered in the management and genetic counselling of patients with these fatal neurodegenerative diseases. 2012 7 The Lancet Neurology 11 323 330 urn:nbn:de:bvb:20-opus-154644 10.1016/S1474-4422(12)70043-1 Institut für Klinische Neurobiologie OPUS4-15456 Wissenschaftlicher Artikel Simon, Christian M.; Rauskolb, Stefanie; Gunnersen, Jennifer M.; Holtmann, Bettina; Drepper, Carsten; Dombert, Benjamin; Braga, Massimiliano; Wiese, Stefan; Jablonka, Sibylle; Pühringer, Dirk; Zielasek, Jürgen; Hoeflich, Andreas; Silani, Vincenzo; Wolf, Eckhard; Kneitz, Susanne; Sommer, Claudia; Toyka, Klaus V.; Sendtner, Michael Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy 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. 2015 14 Acta Neuropathologica 130 373 387 urn:nbn:de:bvb:20-opus-154569 10.1007/s00401-015-1446-8 Frauenklinik und Poliklinik