12 results on '"S Rathke"'
Search Results
2. Two molecular pathways initiate mitochondria-dependent dopaminergic neurodegeneration in experimental Parkinson's disease.
- Author
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Perier C, Bové J, Wu DC, Dehay B, Choi DK, Jackson-Lewis V, Rathke-Hartlieb S, Bouillet P, Strasser A, Schulz JB, Przedborski S, and Vila M
- Subjects
- Animals, Apoptosis, Apoptosis Regulatory Proteins metabolism, Bcl-2-Like Protein 11, DNA Damage, Electron Transport Complex I antagonists & inhibitors, JNK Mitogen-Activated Protein Kinases physiology, Membrane Proteins metabolism, Mice, Mice, Inbred C57BL, Protein Transport, Proto-Oncogene Proteins metabolism, Tumor Suppressor Protein p53 physiology, bcl-2-Associated X Protein metabolism, Mitochondria physiology, Neurodegenerative Diseases etiology, Parkinsonian Disorders pathology, Substantia Nigra pathology
- Abstract
Dysfunction of mitochondrial complex I is associated with a wide spectrum of neurodegenerative disorders, including Parkinson's disease (PD). In rodents, inhibition of complex I leads to degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNpc), as seen in PD, through activation of mitochondria-dependent apoptotic molecular pathways. In this scenario, complex I blockade increases the soluble pool of cytochrome c in the mitochondrial intermembrane space through oxidative mechanisms, whereas activation of pro-cell death protein Bax is actually necessary to trigger neuronal death by permeabilizing the outer mitochondrial membrane and releasing cytochrome c into the cytosol. Activation of Bax after complex I inhibition relies on its transcriptional induction and translocation to the mitochondria. How complex I deficiency leads to Bax activation is currently unknown. Using gene-targeted mice, we show that the tumor suppressor p53 mediates Bax transcriptional induction after PD-related complex I blockade in vivo, but it does not participate in Bax mitochondrial translocation in this model, either by a transcription-independent mechanism or through the induction of BH3-only proteins Puma or Noxa. Instead, Bax mitochondrial translocation in this model relies mainly on the JNK-dependent activation of the BH3-only protein Bim. Targeting either Bax transcriptional induction or Bax mitochondrial translocation results in a marked attenuation of SNpc dopaminergic cell death caused by complex I inhibition. These results provide further insight into the pathogenesis of PD neurodegeneration and identify molecular targets of potential therapeutic significance for this disabling neurological illness.
- Published
- 2007
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3. Transgenic rat model of Huntington's disease.
- Author
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von Hörsten S, Schmitt I, Nguyen HP, Holzmann C, Schmidt T, Walther T, Bader M, Pabst R, Kobbe P, Krotova J, Stiller D, Kask A, Vaarmann A, Rathke-Hartlieb S, Schulz JB, Grasshoff U, Bauer I, Vieira-Saecker AM, Paul M, Jones L, Lindenberg KS, Landwehrmeyer B, Bauer A, Li XJ, and Riess O
- Subjects
- Animals, Animals, Genetically Modified, Cell Nucleus metabolism, DNA, Complementary metabolism, Disease Progression, Glucose metabolism, Huntingtin Protein, Immunohistochemistry, Magnetic Resonance Imaging, Models, Genetic, Nerve Tissue Proteins metabolism, Neurons metabolism, Nuclear Proteins metabolism, Phenotype, Promoter Regions, Genetic, Rats, Time Factors, Tissue Distribution, Tomography, Emission-Computed, Transgenes, Trinucleotide Repeat Expansion, Tryptophan metabolism, Disease Models, Animal, Huntington Disease genetics, Huntington Disease pathology, Nerve Tissue Proteins genetics, Nuclear Proteins genetics
- Abstract
Huntington's disease (HD) is a late manifesting neurodegenerative disorder in humans caused by an expansion of a CAG trinucleotide repeat of more than 39 units in a gene of unknown function. Several mouse models have been reported which show rapid progression of a phenotype leading to death within 3-5 months (transgenic models) resembling the rare juvenile course of HD (Westphal variant) or which do not present with any symptoms (knock-in mice). Owing to the small size of the brain, mice are not suitable for repetitive in vivo imaging studies. Also, rapid progression of the disease in the transgenic models limits their usefulness for neurotransplantation. We therefore generated a rat model transgenic of HD, which carries a truncated huntingtin cDNA fragment with 51 CAG repeats under control of the native rat huntingtin promoter. This is the first transgenic rat model of a neurodegenerative disorder of the brain. These rats exhibit adult-onset neurological phenotypes with reduced anxiety, cognitive impairments, and slowly progressive motor dysfunction as well as typical histopathological alterations in the form of neuronal nuclear inclusions in the brain. As in HD patients, in vivo imaging demonstrates striatal shrinkage in magnetic resonance images and a reduced brain glucose metabolism in high-resolution fluor-deoxy-glucose positron emission tomography studies. This model allows longitudinal in vivo imaging studies and is therefore ideally suited for the evaluation of novel therapeutic approaches such as neurotransplantation.
- Published
- 2003
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4. Progressive loss of striatal neurons causes motor dysfunction in MND2 mutant mice and is not prevented by Bcl-2.
- Author
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Rathke-Hartlieb S, Schlomann U, Heimann P, Meisler MH, Jockusch H, and Bartsch JW
- Subjects
- Animals, Apoptosis, Basal Ganglia Diseases physiopathology, Copper analysis, Corpus Striatum chemistry, Corpus Striatum metabolism, Cytokines biosynthesis, Disease Progression, Humans, Mice, Mice, Inbred C57BL, Mice, Neurologic Mutants, Mice, Transgenic, Movement Disorders genetics, Movement Disorders pathology, Movement Disorders physiopathology, Muscle, Skeletal innervation, Muscle, Skeletal metabolism, Necrosis, Neuroglia pathology, Phenotype, Protein Subunits, Proto-Oncogene Proteins c-bcl-2 biosynthesis, Proto-Oncogene Proteins c-bcl-2 genetics, RNA, Messenger biosynthesis, Receptors, Nicotinic biosynthesis, Receptors, Nicotinic genetics, Zinc analysis, Basal Ganglia Diseases genetics, Basal Ganglia Diseases pathology, Corpus Striatum pathology, Neurons pathology
- Abstract
The mouse mutant "motoneuron disease 2" (MND2, mnd2 on Chr 6) was originally characterized as a spinal muscular atrophy (SMA) because degenerating motoneurons were observed in late stages of the disease. MND2 mutants exhibit a progressive phenotype with neurological symptoms that begin at postnatal day (dP) 20 and include involuntary movements, abnormal postures, akinesis, and death between dP 30 and 40. Unexpectedly, there was no induction of acetylcholine receptor alpha subunit mRNA in skeletal muscle of MND2 mice, an indicator of muscle denervation due to motoneuron loss. Rather, we found a massive loss of striatal neurons beginning at dP 25. Histochemical and ultrastructural analysis revealed nuclear pyknosis, chromatin condensation, and organelle disintegration, combined features of apoptosis and necrosis, characteristic for excitotoxic cell death. Striatal neurodegeneration was accompanied by a pronounced astrogliosis and activation of microglia with macrophage morphology. Motor abnormalities and neuronal loss in MND2 mice were not prevented by neuronal overexpression of a Bcl-2 transgene. Transcripts of several cytokines, including Interleukin-1beta and tumor necrosis factor alpha, were upregulated in the CNS, as well as in lung and spleen, indicating that the mnd2 mutation causes additional pathological effects outside the CNS. Since a 50% reduction in the number of striatal neurons is sufficient to account for the neurological phenotype of MND2 mice, MND2 may be classified as striatal atrophy rather than a primary motor neuron disease. Thus, MND2 mutant mice may provide useful insights into molecular events underlying striatal cell death., (Copyright 2002 Elsevier Science (USA).)
- Published
- 2002
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5. Overexpression of the myelin proteolipid protein leads to accumulation of cholesterol and proteolipid protein in endosomes/lysosomes: implications for Pelizaeus-Merzbacher disease.
- Author
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Simons M, Kramer EM, Macchi P, Rathke-Hartlieb S, Trotter J, Nave KA, and Schulz JB
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- Animals, Biological Transport, Cell Line, Cholic Acids, Cricetinae, Endosomes chemistry, Homeostasis, Lysosomes chemistry, Membrane Microdomains metabolism, Mice, Mice, Transgenic, Myelin Proteolipid Protein genetics, Oligodendroglia cytology, Oligodendroglia metabolism, Solubility, Cholesterol metabolism, Endosomes metabolism, Lysosomes metabolism, Myelin Proteolipid Protein metabolism, Pelizaeus-Merzbacher Disease metabolism
- Abstract
Duplications and overexpression of the proteolipid protein (PLP) gene are known to cause the dysmyelinating disorder Pelizaeus-Merzbacher disease (PMD). To understand the cellular response to overexpressed PLP in PMD, we have overexpressed PLP in BHK cells and primary cultures of oligodendrocytes with the Semliki Forest virus expression system. Overexpressed PLP was routed to late endosomes/lysosomes and caused a sequestration of cholesterol in these compartments. Similar results were seen in transgenic mice overexpressing PLP. With time, the endosomal/lysosomal accumulation of cholesterol and PLP led to an increase in the amount of detergent-insoluble cellular cholesterol and PLP. In addition, two fluorescent sphingolipids, BODIPY-lactosylceramide and -galactosylceramide, which under normal conditions are sorted to the Golgi apparatus, were missorted to perinuclear structures. This was also the case for the lipid raft marker glucosylphosphatidylinositol-yellow fluorescence protein, which under normal steady-state conditions is localized on the plasma membrane and to the Golgi complex. Taken together, we show that overexpression of PLP leads to the formation of endosomal/lysosomal accumulations of cholesterol and PLP, accompanied by the mistrafficking of raft components. We propose that these accumulations perturb the process of myelination and impair the viability of oligodendrocytes.
- Published
- 2002
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6. Sensitivity to MPTP is not increased in Parkinson's disease-associated mutant alpha-synuclein transgenic mice.
- Author
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Rathke-Hartlieb S, Kahle PJ, Neumann M, Ozmen L, Haid S, Okochi M, Haass C, and Schulz JB
- Subjects
- 3,4-Dihydroxyphenylacetic Acid metabolism, Amino Acid Substitution, Animals, Corpus Striatum metabolism, Dopamine metabolism, Homovanillic Acid metabolism, Humans, Mice, Mice, Transgenic, Nerve Tissue Proteins physiology, Neurites metabolism, Neurons drug effects, Neurons metabolism, Parkinsonian Disorders chemically induced, Parkinsonian Disorders metabolism, Parkinsonian Disorders pathology, Promoter Regions, Genetic, Substantia Nigra metabolism, Synucleins, Thy-1 Antigens genetics, Tyrosine 3-Monooxygenase genetics, alpha-Synuclein, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine pharmacology, Nerve Tissue Proteins genetics, Parkinson Disease genetics
- Abstract
Environmental and genetic factors that contribute to the pathogenesis of Parkinson's disease are discussed. Mutations in the alpha-synuclein (alphaSYN ) gene are associated with rare cases of autosomal-dominant Parkinson's disease. We have analysed the dopaminergic system in transgenic mouse lines that expressed mutant [A30P]alphaSYN under the control of a neurone-specific Thy-1 or a tyrosine hydroxylase (TH) promoter. The latter mice showed somal and neuritic accumulation of transgenic [A30P]alphaSYN in TH-positive neurones in the substantia nigra. However, there was no difference in the number of TH-positive neurones in the substantia nigra and the concentrations of catecholamines in the striatum between these transgenic mice and non-transgenic littermates. To investigate whether forced expression of [A30P]alphaSYN increased the sensitivity to putative environmental factors we subjected transgenic mice to a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) regimen. The MPTP-induced decrease in the number of TH-positive neurones in the substantia nigra and the concentrations of catecholamines in the striatum did not differ in any of the [A30P]alphaSYN transgenic mouse lines compared with wild-type controls. These results suggest that mutations and forced expression of alphaSYN are not likely to increase the susceptibility to environmental toxins in vivo.
- Published
- 2001
- Full Text
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7. Protection by synergistic effects of adenovirus-mediated X-chromosome-linked inhibitor of apoptosis and glial cell line-derived neurotrophic factor gene transfer in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease.
- Author
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Eberhardt O, Coelln RV, Kugler S, Lindenau J, Rathke-Hartlieb S, Gerhardt E, Haid S, Isenmann S, Gravel C, Srinivasan A, Bahr M, Weller M, Dichgans J, and Schulz JB
- Subjects
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Animals, Apoptosis drug effects, Caspase Inhibitors, Cells, Cultured, Dopamine metabolism, Drug Synergism, Enzyme Inhibitors pharmacology, Gene Transfer Techniques, Genetic Vectors genetics, Genetic Vectors pharmacology, Glial Cell Line-Derived Neurotrophic Factor, Humans, Male, Mice, Mice, Inbred C57BL, Nerve Tissue Proteins metabolism, Nerve Tissue Proteins pharmacology, Parkinson Disease, Secondary chemically induced, Parkinson Disease, Secondary metabolism, Presynaptic Terminals drug effects, Presynaptic Terminals metabolism, Proteins metabolism, Proteins pharmacology, Rats, Rats, Sprague-Dawley, Substantia Nigra drug effects, Substantia Nigra metabolism, Substantia Nigra pathology, X-Linked Inhibitor of Apoptosis Protein, Adenoviridae genetics, Genetic Therapy methods, Nerve Growth Factors, Nerve Tissue Proteins genetics, Parkinson Disease, Secondary therapy, Proteins genetics
- Abstract
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces clinical, biochemical, and neuropathological changes reminiscent of those occurring in idiopathic Parkinson's disease (PD). Here we show that a peptide caspase inhibitor, N-benzyloxy-carbonyl-val-ala-asp-fluoromethyl ketone, or adenoviral gene transfer (AdV) of a protein caspase inhibitor, X-chromosome-linked inhibitor of apoptosis (XIAP), prevent cell death of dopaminergic substantia nigra pars compacta (SNpc) neurons induced by MPTP or its active metabolite 1-methyl-4-phenylpyridinium in vitro and in vivo. Because the MPTP-induced decrease in striatal concentrations of dopamine and its metabolites does not differ between AdV-XIAP- and control vector-treated mice, this protection is not associated with a preservation of nigrostriatal terminals. In contrast, the combination of adenoviral gene transfer of XIAP and of the glial cell line-derived neurotrophic factor to the striatum provides synergistic effects, rescuing dopaminergic SNpc neurons from cell death and maintaining their nigrostriatal terminals. These data suggest that a combination of a caspase inhibitor, which blocks death, and a neurotrophic factor, which promotes the specific function of the rescued neurons, may be a promising strategy for the treatment of PD.
- Published
- 2000
8. Tumor necrosis factor alpha induces a metalloprotease-disintegrin, ADAM8 (CD 156): implications for neuron-glia interactions during neurodegeneration.
- Author
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Schlomann U, Rathke-Hartlieb S, Yamamoto S, Jockusch H, and Bartsch JW
- Subjects
- ADAM Proteins, Animals, Antigens, Surface analysis, Antigens, Surface genetics, Cell Communication drug effects, Cell Extracts chemistry, Cell Line, Cell Survival drug effects, Central Nervous System metabolism, Central Nervous System pathology, Cytokines biosynthesis, DNA-Binding Proteins antagonists & inhibitors, DNA-Binding Proteins genetics, Disintegrins biosynthesis, Dose-Response Relationship, Drug, Gene Expression drug effects, Heredodegenerative Disorders, Nervous System genetics, Heredodegenerative Disorders, Nervous System pathology, Interferon Regulatory Factor-1, Membrane Proteins analysis, Membrane Proteins genetics, Metalloendopeptidases biosynthesis, Mice, Mice, Inbred C57BL, Mice, Neurologic Mutants, Neuroglia cytology, Neuroglia pathology, Neurons cytology, Neurons pathology, Oligonucleotides, Antisense pharmacology, Organ Specificity genetics, Phosphoproteins antagonists & inhibitors, Phosphoproteins genetics, RNA, Messenger antagonists & inhibitors, RNA, Messenger biosynthesis, Transcriptional Activation, Tumor Necrosis Factor-alpha pharmacology, Antigens, CD, Antigens, Surface biosynthesis, Heredodegenerative Disorders, Nervous System metabolism, Membrane Proteins biosynthesis, Neuroglia metabolism, Neurons metabolism, Tumor Necrosis Factor-alpha metabolism
- Abstract
ADAM proteases, defined by extracellular disintegrin and metalloprotease domains, are involved in protein processing and cell-cell interactions. Using wobbler (WR) mutant mice, we investigated the role of ADAMs in neurodegeneration and reactive glia activation in the CNS. We found that ADAM8 (CD 156), a suspected leukocyte adhesion molecule, is expressed in the CNS and highly induced in affected CNS areas of WR mice, in brainstem and spinal cord. ADAM8 mRNA and protein are found at low levels throughout the normal mouse CNS, in neurons and oligodendrocytes. In the WR CNS regions in which neurodegeneration occurs, ADAM8 is induced in neurons, reactive astrocytes, and activated microglia. Similarly, the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha) is upregulated and shows the same cellular distribution. In primary astrocytes from wild-type and WR mice, in primary cerebellar neurons, and in mouse motoneuron-like NSC19 cells, ADAM8 expression was induced up to 15-fold by mouse TNF-alpha, in a dose-dependent manner. In both cell types, ADAM8 was also induced by human TNF-alpha, indicating that TNF receptor type I (p55) is involved. Induction of ADAM8 mRNA was suppressed by treatment with an interferon-regulating factor 1 (IRF-1) antisense oligonucleotide. We conclude that IRF-1-mediated induction of ADAM8 by TNF-alpha is a signaling pathway relevant for neurodegenerative disorders with glia activation, proposing a role for ADAM8 in cell adhesion during neurodegeneration.
- Published
- 2000
9. Elevated expression of membrane type 1 metalloproteinase (MT1-MMP) in reactive astrocytes following neurodegeneration in mouse central nervous system.
- Author
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Rathke-Hartlieb S, Budde P, Ewert S, Schlomann U, Staege MS, Jockusch H, Bartsch JW, and Frey J
- Subjects
- Animals, Astrocytes immunology, Astrocytes pathology, Cell Line, Cells, Cultured, Central Nervous System pathology, Enzyme Induction genetics, Enzyme Induction immunology, Gene Expression Regulation immunology, Matrix Metalloproteinase 14, Matrix Metalloproteinases, Membrane-Associated, Metalloendopeptidases genetics, Mice, Mice, Inbred C57BL, Mice, Neurologic Mutants, Neurodegenerative Diseases genetics, Neurodegenerative Diseases pathology, RNA, Messenger biosynthesis, Recombinant Proteins pharmacology, Tissue Inhibitor of Metalloproteinase-1 biosynthesis, Tissue Inhibitor of Metalloproteinase-1 genetics, Tissue Inhibitor of Metalloproteinase-2 biosynthesis, Tissue Inhibitor of Metalloproteinase-2 genetics, Tissue Inhibitor of Metalloproteinase-3 biosynthesis, Tissue Inhibitor of Metalloproteinase-3 genetics, Tissue Inhibitor of Metalloproteinases biosynthesis, Tissue Inhibitor of Metalloproteinases genetics, Tumor Necrosis Factor-alpha pharmacology, Up-Regulation genetics, Up-Regulation immunology, Tissue Inhibitor of Metalloproteinase-4, Astrocytes enzymology, Central Nervous System enzymology, Metalloendopeptidases biosynthesis, Neurodegenerative Diseases enzymology
- Abstract
Reactive astrocytes occurring in response to neurodegeneration are thought to play an important role in neuronal regeneration by upregulating the expression of extracellular matrix (ECM) components as well as the ECM degrading metalloproteinases (MMPs). We examined the mRNA levels and cellular distribution of membrane type matrix metalloproteinase 1 (MT1-MMP) and tissue inhibitors 1-4 of MMPs (TIMPs) in brain stem and spinal cord of wobbler (WR) mutant mice affected by progressive neurodegeneration and astrogliosis. MT1-MMP, TIMP-1 and TIMP-3 mRNA levels were elevated, whereas TIMP-2 and TIMP-4 expression was not affected. MT1-MMP was expressed in reactive astrocytes of WR. In primary astrocyte cultures, MT1-MMP mRNA was upregulated by exogeneous tumor necrosis factor alpha. Increased plasma membrane and secreted MMP activities were found in primary WR astrocytes.
- Published
- 2000
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10. A role for polyproline motifs in the spinal muscular atrophy protein SMN. Profilins bind to and colocalize with smn in nuclear gems.
- Author
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Giesemann T, Rathke-Hartlieb S, Rothkegel M, Bartsch JW, Buchmeier S, Jockusch BM, and Jockusch H
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- Amino Acid Motifs, Animals, Cattle, Cyclic AMP Response Element-Binding Protein, HeLa Cells, Humans, Immunohistochemistry, Mice, Mice, Inbred C57BL, Microfilament Proteins genetics, Nerve Tissue Proteins chemistry, Profilins, Protein Binding, RNA, Messenger genetics, RNA, Messenger metabolism, RNA-Binding Proteins, SMN Complex Proteins, Spinal Cord metabolism, Survival of Motor Neuron 1 Protein, Survival of Motor Neuron 2 Protein, Two-Hybrid System Techniques, Cell Nucleus metabolism, Contractile Proteins, Microfilament Proteins metabolism, Nerve Tissue Proteins physiology, Peptides chemistry
- Abstract
Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by the loss of alpha-motoneurons in the spinal cord followed by atrophy of skeletal muscles. SMA-determining candidate genes, SMN1 and SMN2, have been identified on human chromosome 5q. The corresponding SMN protein is expressed ubiquitously. It is coded by seven exons and contains conspicuous proline-rich motifs in its COOH-terminal third (exons 4, 5, and 6). Such motifs are known to bind to profilins (PFNs), small proteins engaged in the control of actin dynamics. We tested whether profilins interact with SMN via its polyproline stretches. Using the yeast two-hybrid system we show that profilins bind to SMN and that this binding depends on its proline-rich motifs. These results were confirmed by coimmunoprecipitation and by in vitro binding studies. Two PFN isoforms, I and II, are known, of which II is characteristic for central nervous system tissue. We show by in situ hybridization that both PFNs are highly expressed in mouse spinal cord and that PFN II is expressed predominantly in neurons. In motoneurons, the primary target of neurodegeneration in SMA, profilins are highly concentrated and colocalize with SMN in the cytoplasm of the cell body and in nuclear gems. Likewise, SMN and PFN I colocalize in gems of HeLa cells. Although SMN interacts with both profilin isoforms, binding of PFN II was stronger than of PFN I in all assays employed. Because the SMN genes are expressed ubiquitously, our findings suggest that the interaction of PFN II with SMN may be involved in neuron-specific effects of SMN mutations.
- Published
- 1999
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11. Spatiotemporal progression of neurodegeneration and glia activation in the wobbler neuropathy of the mouse.
- Author
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Rathke-Hartlieb S, Schmidt VC, Jockusch H, Schmitt-John T, and Bartsch JW
- Subjects
- Alleles, Animals, Astrocytes physiology, Glial Fibrillary Acidic Protein metabolism, Immunohistochemistry, Macrophage Activation, Mice, Mice, Inbred C57BL, Mice, Neurologic Mutants, Microglia physiology, Nerve Degeneration genetics, Neuromuscular Diseases genetics, Polymerase Chain Reaction, Polymorphism, Genetic genetics, Psychomotor Performance physiology, Nerve Degeneration pathology, Neuroglia physiology, Neuromuscular Diseases pathology
- Abstract
The wobbler mouse (phenotype WR; genotype wr/wr) has been investigated as a model for neurodegenerative diseases like SMA and ALS. A new diagnostic marker based on a polymorphism in the closely linked chaperonine gene Cct4 enabled us to diagnose the allelic status at the wr locus within the original background strain C57BL/6. Using this marker, we investigated the spatiotemporal progression of neuropathology in WR mice from postnatal day (d.p.n.) 10 to 60. Neurodegeneration starts at 13 d.p.n. in the thalamus (N. ventralis), in deep cerebellar nuclei, brain stem (N. vestibularis) and spinal cord interneurons. The motor nuclei of spinal nerves and motoneurons degenerate from 15 d.p.n. onward. Reactive astrocytes are observed around 17 d.p.n. in the white and grey matter of the spinal cord. Microgliosis occurs only from 23 d.p.n. onward. Our data demonstrate that in the WR disease, neurodegeneration in thalamus, cerebellum, and brain stem precedes motoneuron degeneration, astrogliosis and microgliosis.
- Published
- 1999
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12. Spinal muscular atrophy gene wobbler of the mouse: evidence from chimeric spinal cord and testis for cell-autonomous function.
- Author
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Augustin M, Heimann P, Rathke S, and Jockusch H
- Subjects
- Animals, Chimera, Female, Gliosis pathology, Male, Mice, Mice, Inbred C57BL, Mice, Inbred NZB, Mice, Neurologic Mutants, Microscopy, Confocal, Microscopy, Electron, Muscular Atrophy, Spinal pathology, Mutation physiology, Polymerase Chain Reaction, RNA, Messenger analysis, Receptors, Cholinergic genetics, Spermatogenesis genetics, Spinal Cord chemistry, Testis ultrastructure, Muscular Atrophy, Spinal genetics, Spinal Cord pathology, Testis pathology
- Abstract
Human hereditary neurodegenerative diseases are genetically and mechanistically very heterogeneous and so are spinal muscular atrophies and cerebellar ataxias in the mouse, despite the common phenomenon of neuronal death. In this species, a number of mutations impair spermiogenesis in addition to neuron survival. Among these, the wobbler mutation on proximal chromosome 11 of the mouse leads to motoneuron degeneration in brain stem and spinal cord and to a defect of spermiogenesis. Chimeric mice of the type wr?/wr? <--> +/+ were produced, and their allelic status at the wr locus was determined by PCR diagnosis of a closely linked marker. Two overt chimeras, one female (XX <--> XX) and one male (XY <--> XY) were identified as wr/wr <--> +/+ and analyzed with respect to their pathological phenotype. Although there was patchy astrogliosis in the spinal cords of both chimeras, their motor performances were overtly normal and muscles were without signs of denervation. The male's testes revealed a mosaic pattern of normal and pathological spermatids. As no progeny was derived from wr spermatids, the spermatocytes appear as a primary target of the wr mutation in testis. Our results argue against a humoral mechanism of the wobbler disease and indicate a cell-autonomous action of the wr gene both in testis and in spinal cord.
- Published
- 1997
- Full Text
- View/download PDF
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