Refine
Has Fulltext
- yes (62)
Is part of the Bibliography
- yes (62) (remove)
Year of publication
Document Type
- Journal article (57)
- Report (2)
- Review (2)
- Book article / Book chapter (1)
Language
- English (62) (remove)
Keywords
- amyotrophic lateral sclerosis (4)
- Neurotrophic factors (3)
- ciliary neurotrophic factor (3)
- spinal muscular atrophy (3)
- BDNF (2)
- CNTF (2)
- RNA (2)
- Schwann cells (2)
- TrkB (2)
- autophagy (2)
- motoneurons (2)
- neuromuscular junction (2)
- neurons (2)
- spinal cord (2)
- synaptic plasticity (2)
- 3D cell culture (1)
- Aging (1)
- Alzheimer's disease (1)
- Alzheimers disease (1)
- Alzheimer’s disease (1)
- Amyotrophic-lateral-sclerosis (1)
- Associative learning (1)
- Astrocytes ; Schwann cells ; Interferon-gamma ; Fibroblast growth factor ; Cyclic AMP (1)
- Axon degeneration (1)
- Axon growth (1)
- Axonal degeneration (1)
- Axonal transport (1)
- BDNF stimulation (1)
- BSTA (1)
- Brain (1)
- C. elegans (1)
- C9orf72 (1)
- Cells (1)
- DAPI staining (1)
- DNA repeat expansion (1)
- DRD1 (1)
- Diabetic polyneuropathy (1)
- Drosophilia (1)
- Exercise (1)
- FGF-5 (1)
- Facial Nerve Transection (1)
- Fear conditioning (1)
- Fibroblast Growth Factor (1)
- GPCR (1)
- Glutamatergic synapses (1)
- Hippocampus (1)
- IGF-I (1)
- Immunopanning (1)
- Insulinlike Growth Factor (1)
- Intermediate filaments (1)
- Lacking neurofilaments (1)
- MAP1B (1)
- Microtubules (1)
- Missense mutation (1)
- Molecular neuroscience (1)
- Motoneuron disease (1)
- Motor behaviour (1)
- Motor nerve biopsy (1)
- Motor neuron disease; Ciliary neurotrophic factor; Brain-derived neurotrophic factor; Animal models; Neurotrophic factors (1)
- Mouse model (1)
- Mus spretus (1)
- NGF gene family (1)
- NMJ–neuromuscular junction (1)
- Nervenzelle (1)
- Neurobiologie (1)
- Neurofilament (1)
- Neuropathy (1)
- Neurotrophin (1)
- Object recognition (1)
- PKB/Akt phosphorylation (1)
- PLEKHG5 (1)
- Phosphorylation (1)
- Plasma-membrane (1)
- Pleckstrin homology containing family member 5 (Plekhg5) (1)
- Progressive motor neuronopathy (1)
- Protein kinase B (1)
- RNA splicing (1)
- RNA transport (1)
- RNA-binding proteins (1)
- Rictor-mTOR complex (1)
- SAP47 gene (1)
- SMN (1)
- SMN granules (1)
- Spinal Muscular-arthropy (1)
- Stat3 (1)
- Stathmin (1)
- Syap1 knockout (1)
- Syap1 localization (1)
- Tdp-43 (1)
- Transcription (1)
- Transgenic mice (1)
- Vascular plasticity (1)
- Viability (1)
- YB-1 (1)
- actin messenger RNA (1)
- adenocarcinoma of the lung (1)
- apoptosis (1)
- axonal degeneration (1)
- axonal transcriptome (1)
- axons (1)
- basal ganglia (1)
- cerebral amyloid angiopathy (1)
- cerebral blood flow (1)
- cerebral small vessel disease (1)
- chick (1)
- ciliary neuron (1)
- ciliary neurotrophic factor (CNTF) (1)
- ciliary-neurotrophic factor (1)
- comet assay (1)
- cortico-striatal synapse (1)
- cross-sectional studies (1)
- cytosol (1)
- dSPN (1)
- degeneration (1)
- demyelination (1)
- determining gene-product (1)
- direct pathway (1)
- dynamics of ribosomal assembly (1)
- early-onset predictors (1)
- electron tomography (1)
- enrichment (1)
- exercise (1)
- factor prevents (1)
- frontotemporal dementia (1)
- fused in sarcoma (1)
- gene targeting (1)
- genome wide (1)
- genome-wide association studies (1)
- hippocampus (1)
- homologous recombination (1)
- hypertensive arteriopathy (1)
- iPSC (induced pluripotent stem cells) (1)
- immune response (1)
- immunoprecipitation (1)
- injury (1)
- insulin (1)
- insulin-likegrowth factor I (1)
- interacts (1)
- interleukin 6 (1)
- interspeific backcross (1)
- intravital imaging (1)
- lIF (1)
- linkage (1)
- lung and intrathoracic tumors (1)
- medicine (1)
- memory (1)
- metastasis (1)
- mild cognitive impairment (1)
- molecular neuroscience (1)
- motoneuron (1)
- motoneuron (MN) (1)
- motoneuron disease (1)
- motor axons (1)
- motor learning (1)
- motor neuron degeneration (1)
- mulitple-sclerosis patients (1)
- myelin (1)
- nerve lesion (1)
- neurofilaments (1)
- neuron migration (1)
- neurotrophic factor (1)
- neurotrophic molecules (1)
- neurotrophins (1)
- nicotinamide (1)
- non-small cell lung cancer (1)
- nonneuronaI cells (1)
- nuclear ribonucleoprotein-R (1)
- presynaptic ER dynamics (1)
- programmed cell death (1)
- protein interactions (1)
- rat (1)
- receptor (1)
- recombinant proteins (1)
- regulation (1)
- restriction fragment length polymorphism (1)
- secondary lung tumors (1)
- skeletal muscle (1)
- spontaneously hypertensive stroke-prone rat (1)
- subcellular trafficking (1)
- survival (1)
- synaptic vesicles (1)
- thoracic diaphragm (1)
- transactivation (1)
- transcription-3 (STAT3) (1)
- uper-resolution array tomography (1)
- vector cloning (1)
- β-actin mRNA (1)
Institute
- Institut für Klinische Neurobiologie (59)
- Theodor-Boveri-Institut für Biowissenschaften (5)
- Neurologische Klinik und Poliklinik (4)
- Institut für Anatomie und Zellbiologie (3)
- Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie (2)
- Frauenklinik und Poliklinik (1)
- Institut für Psychologie (1)
- Lehrstuhl für Biochemie (1)
- Medizinische Klinik und Poliklinik II (1)
Neurofilament depletion improves microtubule dynamics via modulation of Stat3/stathmin signaling
(2016)
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.
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.
Motoneurons played an essential role in establishing the concept of target-mediated support of innervating neurons. However, it took several decades until molecules were identined which trophically support motoneurons in vitro and in vivo. The most potent molecule identined so far is ciliary neurotrophic factor (CNTF). It is expressed as a cytosolic molecule in myelinating Schwann cells rather than in skeletal muscle in the postnatal period and therefore does not qualify as a target-derived neurotrophic factor regulating motoneuron survival during embryonic development. However, the inactivation of CNTF by gene targeting experiments results in progressive atrophy and degeneration of motoneurons, demonstrating that CNTF plays an essential role as a maintenance factor for motoneurons postnatally. Secretory molecules which are expressed in skeletal muscle during embryonic development and which support motoneurons in culture and partially also in vivo include members of the NGF gene family (BDNF, NT-3, NT-4/S) , FGF-S, IGF-I, and UF. The evaluation of the physiological importance of these molecules is under investigation.
Local axonal function of STAT3 rescues axon degeneration in the pmn model of motoneuron disease
(2012)
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.
CILIARY neurotrophic factor (CNTF) was originally characterized as a survival factor for chick ciliary neurons in vitro. More recently, it was shown to promote the survival of a variety of otherneuronal cell types and to affect the differentiation of E7 chick sympathetic neurons by inhibiting their proliferation and by inducing the expression of yasoactiYe intestinal peptide immunoreactiyity (VIP-IR). In cultures of dissociated sympathetic neurons from newborn rats, CNTF induces cholinergic differentiation as shown by increased levels of choline acetyltransferase (ChAT.
Ciliary neurotrophic factor (CNTF) is a potent survival molecule for a variety of embryonic neurons in culture. The developmental expression of CNTF occurs clearly after the time period of the physiological cell death of CNTF-responsive neurons. This, together with the sites of expression, excludes CNTF as a target-derived neuronal survival factor, at least in rodents. However, CNTF also participates in the induction of type 2 astrocyte differentiation in vitro. Here we demonstrate that the time course of the expression of CNTF-mRNA and protein in the rat optic nerve (as evaluated by quantitative Northern blot analysis and biological activity, respectively) is compatible with such a glial differentiation function of CNTF in vivo. We also show that the type 2 astrocyte-inducing- activity previously demonstrated in optic nerve extract can be precipitated by an antiserum against CNTF. Immunohistochemical analysis of astrocytes in vitro and in vivo demonstrates that the expression of CNTF is confined to a subpopulation of type 1 astrocytes. The olfactory bulb of adult rats has comparably high levels of CNTF to the optic nerve, and here again, CNTF-immunoreactivity is localized in a subpopulation of astrocytes. However, the postnatal expression of CNTF in the olfactory bulb occurs later than in the optic nerve. In other brain regions both CNTF-mRNA and protein levels are much lower.
Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy
(2015)
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.
The survival and functional maintenance of spinal motoneurons, both during the period of developmental cell death and in adulthood, have been shown to be dependent on trophic factors. In vitro experiments have previously been used to identify several survival factors for motoneurons, including CNTF, UF, and members of the neurotrophin, FGF, and IGF gene families. Some of these factors have also been shown to be active in vivo, either on chick motoneurons during embryonic development or on lesioned facial and spinal motoneurons of the newborn rat. Here we demonstrate that lesioned newborn rat facial motoneurons can be rescued by NT-4/5, IGF-I, and UF. Furthermore, in contrast to chick motoneurons, the survival of isolated embryonic rat motoneurons can be maintained by the neurotrophins BDNF, NT-3, and NT-4/5. IGF-I and FGF-5 were also active in this system, each supporting more than 50% of the originally plated neurons. The responsiveness of motoneurons to multiple factors in vitro and in vivo suggests that motoneuron survival and function are regulated by the coordinated actions of members of different gene families.
Motoneurons innervating the skeletal musculature were among the first neurons shown to require the presence of their target cells to develop appropriatelyl,2. But the characterization of molecules allowing motoneuron survival has been difficult. Ciliary neurotrophic factor prevents the death of motoneurons3-6, but its gene is not expressed during development7. Although the presence of a neurotrophin receptor on developing motoneurons8-1O has suggested a role for neurotrophins, none could be shown to promote motoneuron survival in vitro3. We report here that brainderived neurotrophic factor can prevent the death of axotomized motoneurons in newborn rats, suggesting a role for this neurotrophin for motoneuron survival in vivo.