22 results on '"Bräuer A"'
Search Results
2. Differential Upregulation and Functional Activity of S1PR1 in Human Peripheral Blood Basophils of Atopic Patients
- Author
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Natalie Gray, Maren M. Limberg, Daniela Wiebe, Tobias Weihrauch, Anna Langner, Nicola Brandt, Anja U. Bräuer, and Ulrike Raap
- Subjects
basophils ,S1P ,S1PR ,atopy ,apoptosis ,chemotaxis ,Organic Chemistry ,General Medicine ,Catalysis ,Computer Science Applications ,Up-Regulation ,Basophils ,Inorganic Chemistry ,Receptors, Lysosphingolipid ,Sphingosine ,Humans ,Physical and Theoretical Chemistry ,Lysophospholipids ,Molecular Biology ,Sphingosine-1-Phosphate Receptors ,Spectroscopy - Abstract
Basophils are key effector cells in atopic diseases, and the signaling sphingolipid Sphigosine-1-phosphate (S1P) is emerging as an important mediator in these conditions. The possible interaction of S1P and basophils and the resulting biological effects have not yet been studied. We hypothesize that S1P influences the function of basophils in atopy and aim to elucidate the modes of interaction. S1P receptor (S1PR) expression in human peripheral blood basophils from atopic and non-atopic patients was assessed through qRT-PCR and flow cytometry analysis. Functional effects of S1P were assessed through a basophil activation test (BAT), calcium flux, apoptosis, and chemotaxis assays. Immunofluorescence staining was performed to visualize intracellular S1P. Human basophils express S1PR1, S1PR2, S1PR3, and S1PR4 on the mRNA level. 0.1 µM S1P have anti-apoptotic, while 10 µM exhibits apoptotic effects on basophils. Basophils from atopic patients show less chemotactic activity in response to S1P than those from healthy donors. Protein expression of S1PR1 is downregulated in atopic patients, and basophils in lesional AD skin possess intracellular S1P. These findings suggest that the interaction of S1P and basophils might be an important factor in the pathophysiology of atopy.
- Published
- 2022
3. PRG3 and PRG5 C-Termini: Important Players in Early Neuronal Differentiation
- Author
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Nicola Brandt, Jan Philipp Willmer, Maurilyn S. Ayon-Olivas, Veronika Banicka, Martin Witt, Andreas Wree, Isabel Groß, Anne Gläser, Jens Hausmann, and Anja U. Bräuer
- Subjects
Inorganic Chemistry ,Neurons ,Organic Chemistry ,Brain ,General Medicine ,Physical and Theoretical Chemistry ,Molecular Biology ,PRG3/LPPR1 ,PRG5/LPPR5 ,PRG4/LPPR2 ,neuronal outgrowth ,hippocampal neurons ,Hippocampus ,Spectroscopy ,Catalysis ,Computer Science Applications - Abstract
The functional importance of neuronal differentiation of the transmembrane proteins’ plasticity-related genes 3 (PRG3) and 5 (PRG5) has been shown. Although their sequence is closely related, they promote different morphological changes in neurons. PRG3 was shown to promote neuritogenesis in primary neurons; PRG5 contributes to spine induction in immature neurons and the regulation of spine density and morphology in mature neurons. Both exhibit intracellularly located C-termini of less than 50 amino acids. Varying C-termini suggested that these domains shape neuronal morphology differently. We generated mutant EGFP-fusion proteins in which the C-termini were either swapped between PRG3 and PRG5, deleted, or fused to another family member, plasticity-related gene 4 (PRG4), that was recently shown to be expressed in different brain regions. We subsequently analyzed the influence of overexpression in immature neurons. Our results point to a critical role of the PRG3 and PRG5 C-termini in shaping early neuronal morphology. However, the results suggest that the C-terminus alone might not be sufficient for promoting the morphological effects induced by PRG3 and PRG5.
- Published
- 2022
4. PRG3 and PRG5 C-Termini: Important Players in Early Neuronal Differentiation
- Author
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Brandt, Nicola, primary, Willmer, Jan Philipp, additional, Ayon-Olivas, Maurilyn S., additional, Banicka, Veronika, additional, Witt, Martin, additional, Wree, Andreas, additional, Groß, Isabel, additional, Gläser, Anne, additional, Hausmann, Jens, additional, and Bräuer, Anja U., additional
- Published
- 2022
- Full Text
- View/download PDF
5. Microbeam Irradiation as a Simultaneously Integrated Boost in a Conventional Whole-Brain Radiotherapy Protocol
- Author
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Jaekel, Felix, primary, Bräuer-Krisch, Elke, additional, Bartzsch, Stefan, additional, Laissue, Jean, additional, Blattmann, Hans, additional, Scholz, Marten, additional, Soloviova, Julia, additional, Hildebrandt, Guido, additional, and Schültke, Elisabeth, additional
- Published
- 2022
- Full Text
- View/download PDF
6. The Potential Role of SP-G as Surface Tension Regulator in Tear Film: From Molecular Simulations to Experimental Observations
- Author
-
Schicht, Martin, primary, Riedlová, Kamila, additional, Kukulka, Mercedes, additional, Li, Wenyue, additional, Scheer, Aurelius, additional, Garreis, Fabian, additional, Jacobi, Christina, additional, Paulsen, Friedrich, additional, Cwiklik, Lukasz, additional, and Bräuer, Lars, additional
- Published
- 2022
- Full Text
- View/download PDF
7. Aβ-Induced Alterations in Membrane Lipids Occur before Synaptic Loss Appears
- Author
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Van Bulck, Michiel, primary, Brandt, Nicola, additional, Claus, Ralf A., additional, Gräler, Markus, additional, and Bräuer, Anja U., additional
- Published
- 2022
- Full Text
- View/download PDF
8. Aβ-Induced Alterations in Membrane Lipids Occur before Synaptic Loss Appears
- Author
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Michiel, Van Bulck, Nicola, Brandt, Ralf A, Claus, Markus, Gräler, and Anja U, Bräuer
- Subjects
Mice, Inbred C57BL ,Neurons ,Membrane Lipids ,Mice ,Amyloid beta-Peptides ,Alzheimer Disease ,Synapses ,Animals ,Hippocampus ,Cells, Cultured - Abstract
Loss of active synapses and alterations in membrane lipids are crucial events in physiological aging as well as in neurodegenerative disorders. Both are related to the abnormal aggregation of amyloid-beta (Aβ) species, generally known as amyloidosis. There are two major known human Aβ species: Aβ
- Published
- 2022
9. Identification of Brain-Specific Treatment Effects in NPC1 Disease by Focusing on Cellular and Molecular Changes of Sphingosine-1-Phosphate Metabolism
- Author
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Gläser, Anne, Hammerl, Franziska, Gräler, Markus H., Coldewey, Sina M., Völkner, Christin, Frech, Moritz J., Yang, Fan, Luo, Jiankai, Tönnies, Eric, Halbach, Oliver von Bohlen und, Brandt, Nicola, Heimes, Diana, Neßlauer, Anna-Maria, Korenke, Georg Christoph, Owczarek-Lipska, Marta, Neidhardt, John, Rolfs, Arndt, Wree, Andreas, Witt, Martin, and Bräuer, Anja Ursula
- Subjects
Adult ,congenital, hereditary, and neonatal diseases and abnormalities ,1-Deoxynojirimycin ,brain ,Induced Pluripotent Stem Cells ,S1P ,Article ,Niemann–Pick disease type C1 ,sphingosine-1-phosphate receptors ,HPTLC ,lcsh:Chemistry ,Mice ,Young Adult ,Niemann-Pick C1 Protein ,Sphingosine ,hemic and lymphatic diseases ,fibroblasts ,Animals ,Humans ,Glycoside Hydrolase Inhibitors ,lcsh:QH301-705.5 ,mass spectrometry ,Mice, Knockout ,sphingolipids ,Intracellular Signaling Peptides and Proteins ,nutritional and metabolic diseases ,Niemann-Pick Disease, Type C ,qRT-PCR ,Disease Models, Animal ,lcsh:Biology (General) ,lcsh:QD1-999 ,Mutation ,lipids (amino acids, peptides, and proteins) ,Lysophospholipids ,white matter - Abstract
Niemann&ndash, Pick type C1 (NPC1) is a lysosomal storage disorder, inherited as an autosomal-recessive trait. Mutations in the Npc1 gene result in malfunction of the NPC1 protein, leading to an accumulation of unesterified cholesterol and glycosphingolipids. Beside visceral symptoms like hepatosplenomegaly, severe neurological symptoms such as ataxia occur. Here, we analyzed the sphingosine-1-phosphate (S1P)/S1P receptor (S1PR) axis in different brain regions of Npc1&minus, /&minus, mice and evaluated specific effects of treatment with 2-hydroxypropyl-&beta, cyclodextrin (HP&beta, CD) together with the iminosugar miglustat. Using high-performance thin-layer chromatography (HPTLC), mass spectrometry, quantitative real-time PCR (qRT-PCR) and western blot analyses, we studied lipid metabolism in an NPC1 mouse model and human skin fibroblasts. Lipid analyses showed disrupted S1P metabolism in Npc1&minus, mice in all brain regions, together with distinct changes in S1pr3/S1PR3 and S1pr5/S1PR5 expression. Brains of Npc1&minus, mice showed only weak treatment effects. However, side effects of the treatment were observed in Npc1+/+ mice. The S1P/S1PR axis seems to be involved in NPC1 pathology, showing only weak treatment effects in mouse brain. S1pr expression appears to be affected in human fibroblasts, induced pluripotent stem cells (iPSCs)-derived neural progenitor and neuronal differentiated cells. Nevertheless, treatment-induced side effects make examination of further treatment strategies indispensable.
- Published
- 2020
10. Human Spinal Motor Neurons Are Particularly Vulnerable to Cerebrospinal Fluid of Amyotrophic Lateral Sclerosis Patients
- Author
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Hannes Glaß, Andreas Hermann, Jared Sterneckert, René Günther, and Stefan Bräuer
- Subjects
0301 basic medicine ,Male ,amyotrophic lateral sclerosis ,Golgi Apparatus ,Disease ,lcsh:Chemistry ,fused in sarcoma ,0302 clinical medicine ,Cerebrospinal fluid ,superoxide dismutase 1 ,Medicine ,Amyotrophic lateral sclerosis ,Induced pluripotent stem cell ,lcsh:QH301-705.5 ,Spectroscopy ,Cerebrospinal Fluid ,Motor Neurons ,physiopathology [Amyotrophic Lateral Sclerosis] ,General Medicine ,Middle Aged ,Pathophysiology ,Computer Science Applications ,medicine.anatomical_structure ,Spinal Cord ,ddc:540 ,symbols ,Female ,Golgi fragmentation ,Adult ,Cell type ,metabolism [Spinal Cord] ,pathology [Motor Neurons] ,Induced Pluripotent Stem Cells ,physiopathology [Spinal Cord] ,Protein Aggregation, Pathological ,Catalysis ,Article ,cerebrospinal fluid ,Inorganic Chemistry ,03 medical and health sciences ,symbols.namesake ,Humans ,Physical and Theoretical Chemistry ,Molecular Biology ,business.industry ,metabolism [Amyotrophic Lateral Sclerosis] ,Organic Chemistry ,metabolism [Motor Neurons] ,Golgi apparatus ,Motor neuron ,medicine.disease ,030104 developmental biology ,pathology [Golgi Apparatus] ,lcsh:Biology (General) ,lcsh:QD1-999 ,ALS ,business ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Amyotrophic lateral sclerosis (ALS) is the most common and devastating motor neuron (MN) disease. Its pathophysiological cascade is still enigmatic. More than 90% of ALS patients suffer from sporadic ALS, which makes it specifically demanding to generate appropriate model systems. One interesting aspect considering the seeding, spreading and further disease development of ALS is the cerebrospinal fluid (CSF). We therefore asked whether CSF from sporadic ALS patients is capable of causing disease typical changes in human patient-derived spinal MN cultures and thus could represent a novel model system for sporadic ALS. By using induced pluripotent stem cell (iPSC)-derived MNs from healthy controls and monogenetic forms of ALS we could demonstrate a harmful effect of ALS-CSF on healthy donor-derived human MNs. Golgi fragmentation&mdash, a typical finding in lower organism models and human postmortem tissue&mdash, was induced solely by addition of ALS-CSF, but not control-CSF. No other neurodegenerative hallmarks&mdash, including pathological protein aggregation&mdash, were found, underpinning Golgi fragmentation as early event in the neurodegenerative cascade. Of note, these changes occurred predominantly in MNs, the cell type primarily affected in ALS. We thus present a novel way to model early features of sporadic ALS.
- Published
- 2020
11. Human Spinal Motor Neurons Are Particularly Vulnerable to Cerebrospinal Fluid of Amyotrophic Lateral Sclerosis Patients
- Author
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Bräuer, Stefan, primary, Günther, René, additional, Sterneckert, Jared, additional, Glaß, Hannes, additional, and Hermann, Andreas, additional
- Published
- 2020
- Full Text
- View/download PDF
12. Current Challenges in Understanding the Cellular and Molecular Mechanisms in Niemann–Pick Disease Type C1
- Author
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Bräuer, Anja U., Kuhla, Angela, Holzmann, Carsten, Wree, Andreas, and Witt, Martin
- Subjects
electron microscopy, cholesterol homeostasis ,treatment ,neurodegeneration ,RT-PCR ,Biological Transport ,Niemann-Pick Disease, Type C ,lipid storage disorder ,Review ,Lipid Metabolism ,histology ,lcsh:Chemistry ,Disease Models, Animal ,Mice ,cyclodextrin ,lcsh:Biology (General) ,lcsh:QD1-999 ,Organ Specificity ,Animals ,Humans ,miglustat ,Disease Susceptibility ,lcsh:QH301-705.5 - Abstract
Rare diseases are a heterogeneous group of very different clinical syndromes. Their most common causes are defects in the hereditary material, and they can therefore be passed on to descendants. Rare diseases become manifest in almost all organs and often have a systemic expressivity, i.e., they affect several organs simultaneously. An effective causal therapy is often not available and can only be developed when the underlying causes of the disease are understood. In this review, we focus on Niemann−Pick disease type C1 (NPC1), which is a rare lipid-storage disorder. Lipids, in particular phospholipids, are a major component of the cell membrane and play important roles in cellular functions, such as extracellular receptor signaling, intracellular second messengers and cellular pressure regulation. An excessive storage of fats, as seen in NPC1, can cause permanent damage to cells and tissues in the brain and peripheral nervous system, but also in other parts of the body. Here, we summarize the impact of NPC1 pathology on several organ systems, as revealed in experimental animal models and humans, and give an overview of current available treatment options.
- Published
- 2019
13. Evaluation of Two Liver Treatment Strategies in a Mouse Model of Niemann–Pick-Disease Type C1
- Author
-
Ebner, Lynn, Gläser, Anne, Bräuer, Anja, Witt, Martin, Wree, Andreas, Rolfs, Arndt, Frank, Marcus, Vollmar, Brigitte, and Kuhla, Angela
- Subjects
1-Deoxynojirimycin ,Pregnanolone ,NPC1 mutant ,Article ,lcsh:Chemistry ,Mice ,Niemann-Pick C1 Protein ,Animals ,Humans ,PPAR alpha ,lcsh:QH301-705.5 ,Mice, Knockout ,Mice, Inbred BALB C ,liver dysfunction ,Intracellular Signaling Peptides and Proteins ,Proteins ,nutritional and metabolic diseases ,Niemann-Pick Disease, Type C ,allopregnanolone ,2-Hydroxypropyl-beta-cyclodextrin ,Disease Models, Animal ,Cholesterol ,Liver ,cyclodextrin ,lcsh:Biology (General) ,lcsh:QD1-999 ,Drug Therapy, Combination ,lipids (amino acids, peptides, and proteins) ,miglustat ,Acyl-CoA Oxidase ,Hepatomegaly - Abstract
Niemann–Pick-disease type C1 (NPC1) is an autosomal-recessive cholesterol-storage disorder. Besides other symptoms, NPC1 patients develop liver dysfunction and hepatosplenomegaly. The mechanisms of hepatomegaly and alterations of lipid metabolism-related genes in NPC1 disease are still poorly understood. Here, we used an NPC1 mouse model to study an additive hepatoprotective effect of a combination of 2-hydroxypropyl-β-cyclodextrin (HPβCD), miglustat and allopregnanolone (combination therapy) with the previously established monotherapy using HPβCD. We examined transgene effects as well as treatment effects on liver morphology and hepatic lipid metabolism, focusing on hepatic cholesterol transporter genes. Livers of Npc1−/− mice showed hepatic cholesterol sequestration with consecutive liver injury, an increase of lipogenetic gene expression, e.g., HMG-CoA, a decrease of lipolytic gene expression, e.g., pparα and acox1, and a decrease of lipid transporter gene expression, e.g., acat1, abca1 and fatp2. Both, combination therapy and monotherapy, led to a reduction of hepatic lipids and an amelioration of NPC1 liver disease symptoms. Monotherapy effects were related to pparα- and acox1-associated lipolysis/β-oxidation and to fatp2-induced fatty acid transport, whereas the combination therapy additionally increased the cholesterol transport via abca1 and apoE. However, HPβCD monotherapy additionally increased cholesterol synthesis as indicated by a marked increase of the HMG-CoA and srebp-2 mRNA expression, probably as a result of increased hepatocellular proliferation.
- Published
- 2018
14. Glucosylsphingosine Causes Hematological and Visceral Changes in Mice—Evidence for a Pathophysiological Role in Gaucher Disease
- Author
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Lukas, Jan, primary, Cozma, Claudia, additional, Yang, Fan, additional, Kramp, Guido, additional, Meyer, Anja, additional, Neßlauer, Anna-Maria, additional, Eichler, Sabrina, additional, Böttcher, Tobias, additional, Witt, Martin, additional, Bräuer, Anja, additional, Kropp, Peter, additional, and Rolfs, Arndt, additional
- Published
- 2017
- Full Text
- View/download PDF
15. Aβ-Induced Alterations in Membrane Lipids Occur before Synaptic Loss Appears
- Author
-
Van Bulck, Michiel, Brandt, Nicola, Claus, Ralf A., Gräler, Markus, Bräuer, Anja U., and European Commission
- Subjects
Alzheimers disease ,Aβ species ,Synapses ,Neurones ,Glia cells ,Membrane lipids ,Cell-communication - Abstract
Loss of active synapses and alterations in membrane lipids are crucial events in physiological aging as well as in neurodegenerative disorders. Both are related to the abnormal aggregation of amyloid-beta (Aβ) species, generally known as amyloidosis. There are two major known human Aβ species: Aβ(1–40) and Aβ(1–42). However, which of these species have more influence on active synapses and membrane lipids is still poorly understood. Additionally, the time-dependent effect of Aβ species on alterations in membrane lipids of hippocampal neurones and glial cells remains unknown. Therefore, our study contributes to a better understanding of the role of Aβ species in the loss of active synapses and the dysregulation of membrane lipids in vitro. We showed that Aβ(1–40) or Aβ(1–42) treatment influences membrane lipids before synaptic loss appears and that the loss of active synapses is not dependent on the Aβ species. Our lipidomic data analysis showed early changes in specific lipid classes such as sphingolipid and glycerophospholipid neurones. Our results underscore the potential role of lipids as a possible early diagnostic biomarker in amyloidosis-related disorders., This research was funded by H2020 MSCA-ITN-ETN BBDiag project under grant No. 721281.
- Full Text
- View/download PDF
16. Microbeam Irradiation as a Simultaneously Integrated Boost in a Conventional Whole-Brain Radiotherapy Protocol
- Author
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Felix Jaekel, Elke Bräuer-Krisch, Stefan Bartzsch, Jean Laissue, Hans Blattmann, Marten Scholz, Julia Soloviova, Guido Hildebrandt, and Elisabeth Schültke
- Subjects
microbeam radiotherapy (MRT) ,simultaneously integrated boost (SIB) ,brain tissue tolerance ,F98 glioma cells ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Microbeam radiotherapy (MRT), an experimental high-dose rate concept with spatial fractionation at the micrometre range, has shown a high therapeutic potential as well as good preservation of normal tissue function in pre-clinical studies. We investigated the suitability of MRT as a simultaneously integrated boost (SIB) in conventional whole-brain irradiation (WBRT). A 174 Gy MRT SIB was administered with an array of quasi-parallel, 50 µm wide microbeams spaced at a centre-to-centre distance of 400 µm either on the first or last day of a 5 × 4 Gy radiotherapy schedule in healthy adult C57 BL/6J mice and in F98 glioma cell cultures. The animals were observed for signs of intracranial pressure and focal neurologic signs. Colony counts were conducted in F98 glioma cell cultures. No signs of acute adverse effects were observed in any of the irradiated animals within 3 days after the last irradiation fraction. The tumoricidal effect on F98 cell in vitro was higher when the MRT boost was delivered on the first day of the irradiation course, as opposed to the last day. Therefore, the MRT SIB should be integrated into a clinical radiotherapy schedule as early as possible.
- Published
- 2022
- Full Text
- View/download PDF
17. The Potential Role of SP-G as Surface Tension Regulator in Tear Film: From Molecular Simulations to Experimental Observations
- Author
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Martin Schicht, Kamila Riedlová, Mercedes Kukulka, Wenyue Li, Aurelius Scheer, Fabian Garreis, Christina Jacobi, Friedrich Paulsen, Lukasz Cwiklik, and Lars Bräuer
- Subjects
tear film ,surfactant protein ,surface tension ,ocular surface ,dry eye ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
The ocular surface is in constant interaction with the environment and with numerous pathogens. Therefore, complex mechanisms such as a stable tear film and local immune defense mechanisms are required to protect the eye. This study describes the detection, characterization, and putative role of surfactant protein G (SP-G/SFTA2) with respect to wound healing and surface activity. Bioinformatic, biochemical, and immunological methods were combined to elucidate the role of SP-G in tear film. The results show the presence of SP-G in ocular surface tissues and tear film (TF). Increased expression of SP-G was demonstrated in TF of patients with dry eye disease (DED). Addition of recombinant SP-G in combination with lipids led to an accelerated wound healing of human corneal cells as well as to a reduction of TF surface tension. Molecular modeling of TF suggest that SP-G may regulate tear film surface tension and improve its stability through specific interactions with lipids components of the tear film. In conclusion, SP-G is an ocular surface protein with putative wound healing properties that can also reduce the surface tension of the tear film.
- Published
- 2022
- Full Text
- View/download PDF
18. Identification of Brain-Specific Treatment Effects in NPC1 Disease by Focusing on Cellular and Molecular Changes of Sphingosine-1-Phosphate Metabolism
- Author
-
Anne Gläser, Franziska Hammerl, Markus H. Gräler, Sina M. Coldewey, Christin Völkner, Moritz J. Frech, Fan Yang, Jiankai Luo, Eric Tönnies, Oliver von Bohlen und Halbach, Nicola Brandt, Diana Heimes, Anna-Maria Neßlauer, Georg Christoph Korenke, Marta Owczarek-Lipska, John Neidhardt, Arndt Rolfs, Andreas Wree, Martin Witt, and Anja Ursula Bräuer
- Subjects
Niemann–Pick disease type C1 ,brain ,fibroblasts ,S1P ,sphingosine-1-phosphate receptors ,qRT-PCR ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Niemann–Pick type C1 (NPC1) is a lysosomal storage disorder, inherited as an autosomal-recessive trait. Mutations in the Npc1 gene result in malfunction of the NPC1 protein, leading to an accumulation of unesterified cholesterol and glycosphingolipids. Beside visceral symptoms like hepatosplenomegaly, severe neurological symptoms such as ataxia occur. Here, we analyzed the sphingosine-1-phosphate (S1P)/S1P receptor (S1PR) axis in different brain regions of Npc1−/− mice and evaluated specific effects of treatment with 2-hydroxypropyl-β-cyclodextrin (HPβCD) together with the iminosugar miglustat. Using high-performance thin-layer chromatography (HPTLC), mass spectrometry, quantitative real-time PCR (qRT-PCR) and western blot analyses, we studied lipid metabolism in an NPC1 mouse model and human skin fibroblasts. Lipid analyses showed disrupted S1P metabolism in Npc1−/− mice in all brain regions, together with distinct changes in S1pr3/S1PR3 and S1pr5/S1PR5 expression. Brains of Npc1−/− mice showed only weak treatment effects. However, side effects of the treatment were observed in Npc1+/+ mice. The S1P/S1PR axis seems to be involved in NPC1 pathology, showing only weak treatment effects in mouse brain. S1pr expression appears to be affected in human fibroblasts, induced pluripotent stem cells (iPSCs)-derived neural progenitor and neuronal differentiated cells. Nevertheless, treatment-induced side effects make examination of further treatment strategies indispensable.
- Published
- 2020
- Full Text
- View/download PDF
19. Human Spinal Motor Neurons Are Particularly Vulnerable to Cerebrospinal Fluid of Amyotrophic Lateral Sclerosis Patients
- Author
-
Stefan Bräuer, René Günther, Jared Sterneckert, Hannes Glaß, and Andreas Hermann
- Subjects
amyotrophic lateral sclerosis ,ALS ,cerebrospinal fluid ,Golgi fragmentation ,superoxide dismutase 1 ,fused in sarcoma ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Amyotrophic lateral sclerosis (ALS) is the most common and devastating motor neuron (MN) disease. Its pathophysiological cascade is still enigmatic. More than 90% of ALS patients suffer from sporadic ALS, which makes it specifically demanding to generate appropriate model systems. One interesting aspect considering the seeding, spreading and further disease development of ALS is the cerebrospinal fluid (CSF). We therefore asked whether CSF from sporadic ALS patients is capable of causing disease typical changes in human patient-derived spinal MN cultures and thus could represent a novel model system for sporadic ALS. By using induced pluripotent stem cell (iPSC)-derived MNs from healthy controls and monogenetic forms of ALS we could demonstrate a harmful effect of ALS-CSF on healthy donor-derived human MNs. Golgi fragmentation—a typical finding in lower organism models and human postmortem tissue—was induced solely by addition of ALS-CSF, but not control-CSF. No other neurodegenerative hallmarks—including pathological protein aggregation—were found, underpinning Golgi fragmentation as early event in the neurodegenerative cascade. Of note, these changes occurred predominantly in MNs, the cell type primarily affected in ALS. We thus present a novel way to model early features of sporadic ALS.
- Published
- 2020
- Full Text
- View/download PDF
20. Current Challenges in Understanding the Cellular and Molecular Mechanisms in Niemann–Pick Disease Type C1
- Author
-
Anja U. Bräuer, Angela Kuhla, Carsten Holzmann, Andreas Wree, and Martin Witt
- Subjects
neurodegeneration ,lipid storage disorder ,RT-PCR ,histology ,electron microscopy, cholesterol homeostasis ,miglustat ,cyclodextrin ,treatment ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Rare diseases are a heterogeneous group of very different clinical syndromes. Their most common causes are defects in the hereditary material, and they can therefore be passed on to descendants. Rare diseases become manifest in almost all organs and often have a systemic expressivity, i.e., they affect several organs simultaneously. An effective causal therapy is often not available and can only be developed when the underlying causes of the disease are understood. In this review, we focus on Niemann−Pick disease type C1 (NPC1), which is a rare lipid-storage disorder. Lipids, in particular phospholipids, are a major component of the cell membrane and play important roles in cellular functions, such as extracellular receptor signaling, intracellular second messengers and cellular pressure regulation. An excessive storage of fats, as seen in NPC1, can cause permanent damage to cells and tissues in the brain and peripheral nervous system, but also in other parts of the body. Here, we summarize the impact of NPC1 pathology on several organ systems, as revealed in experimental animal models and humans, and give an overview of current available treatment options.
- Published
- 2019
- Full Text
- View/download PDF
21. Evaluation of Two Liver Treatment Strategies in a Mouse Model of Niemann–Pick-Disease Type C1
- Author
-
Lynn Ebner, Anne Gläser, Anja Bräuer, Martin Witt, Andreas Wree, Arndt Rolfs, Marcus Frank, Brigitte Vollmar, and Angela Kuhla
- Subjects
NPC1 mutant ,liver dysfunction ,miglustat ,allopregnanolone ,cyclodextrin ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Niemann–Pick-disease type C1 (NPC1) is an autosomal-recessive cholesterol-storage disorder. Besides other symptoms, NPC1 patients develop liver dysfunction and hepatosplenomegaly. The mechanisms of hepatomegaly and alterations of lipid metabolism-related genes in NPC1 disease are still poorly understood. Here, we used an NPC1 mouse model to study an additive hepatoprotective effect of a combination of 2-hydroxypropyl-β-cyclodextrin (HPβCD), miglustat and allopregnanolone (combination therapy) with the previously established monotherapy using HPβCD. We examined transgene effects as well as treatment effects on liver morphology and hepatic lipid metabolism, focusing on hepatic cholesterol transporter genes. Livers of Npc1−/− mice showed hepatic cholesterol sequestration with consecutive liver injury, an increase of lipogenetic gene expression, e.g., HMG-CoA, a decrease of lipolytic gene expression, e.g., pparα and acox1, and a decrease of lipid transporter gene expression, e.g., acat1, abca1 and fatp2. Both, combination therapy and monotherapy, led to a reduction of hepatic lipids and an amelioration of NPC1 liver disease symptoms. Monotherapy effects were related to pparα- and acox1-associated lipolysis/β-oxidation and to fatp2-induced fatty acid transport, whereas the combination therapy additionally increased the cholesterol transport via abca1 and apoE. However, HPβCD monotherapy additionally increased cholesterol synthesis as indicated by a marked increase of the HMG-CoA and srebp-2 mRNA expression, probably as a result of increased hepatocellular proliferation.
- Published
- 2018
- Full Text
- View/download PDF
22. Glucosylsphingosine Causes Hematological and Visceral Changes in Mice—Evidence for a Pathophysiological Role in Gaucher Disease
- Author
-
Jan Lukas, Claudia Cozma, Fan Yang, Guido Kramp, Anja Meyer, Anna-Maria Neßlauer, Sabrina Eichler, Tobias Böttcher, Martin Witt, Anja U. Bräuer, Peter Kropp, and Arndt Rolfs
- Subjects
sphingolipids ,glucocerebrosidase ,biomarker ,storage disease pathology ,chemically-induced phenotype ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Glucosylceramide and glucosylsphingosine are the two major storage products in Gaucher disease (GD), an inherited metabolic disorder caused by a deficiency of the lysosomal enzyme glucocerebrosidase. The build-up of glucosylceramide in the endoplasmic reticulum and prominent accumulation in cell lysosomes of tissue macrophages results in decreased blood cell and platelet counts, and skeletal abnormalities. The pathological role of the deacylated form of glucosylceramide, glucosylsphingosine (lyso-Gb1), a recently identified sensitive and specific biomarker for GD, is not well investigated. We established a long-term infusion model in C57BL/6JRj mice to examine the effect of lyso-Gb1 on representative hallmark parameters of GD. Mice received lyso-Gb1 at a dosage of 10 mg·kg−1 per day as a continuous subcutaneous administration, and were routinely checked for blood lyso-Gb1 levels using liquid chromatography-multiple reaction monitoring mass spectrometry (LC/MRM-MS) measurements at four-weekly intervals throughout treatment. The C57BL/6JRj mice showed a stable increase of lyso-Gb1 up to->500-fold greater than the normal reflecting concentrations seen in moderately to severely affected patients. Furthermore, lyso-Gb1 accumulated in peripheral tissues. The mice developed hematological symptoms such as reduced hemoglobin and hematocrit, increased spleen weights and a slight inflammatory tissue response after eight weeks of treatment. The above findings indicate a measurable visceral and hematological response in treated mice that suggests a role for lyso-Gb1 in the development of peripheral signs of GD.
- Published
- 2017
- Full Text
- View/download PDF
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