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  • 1
    Language: English
    In: The Lancet, 2004, Vol.364(9441), pp.1196-1197
    Description: Transmissible spongiform encephalopathies (TSE), or prion diseases, are fatal neurodegenerative disorders that affect human beings and other animals.1 Prion diseases are characterised by the accumulation of PrP^sup Sc^, an abnormal form of the host-encoded prion protein.2 Transmission of these diseases between human beings can occur-eg, via neurosurgical instruments.3 Interspecies transmission of bovine spongiform encephalopathy (BSE) prions to human beings almost certainly resulted in a novel TSE, variant Creutzfeldt-Jakob disease (vCJD).4 Since 1995, 142 individuals have died of vCJD in the UK.5 The incidence of vCJD in the UK seems to be stabilising, or even declining; however, uncertainty still prevails as to whether there will be an epidemic.6 The prominent lymphoid tropism of vCJD prions distinguishes this type of TSE from other prion diseases in human beings, and detection of prions in lymphoid organs might be a marker for vCJD.7,8 Until now, studies aimed at predicting the prevalence of vCJD in the UK were done with archived tissue specimens, mainly from appendices and tonsils, and relied on histological methods to assess the presence of pathological prion protein.9,10
    Keywords: Medicine
    ISSN: 0140-6736
    E-ISSN: 1474-547X
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  • 2
    Language: English
    In: PLoS ONE, 2011, Vol.6(9), p.e24624
    Description: The cellular prion protein (PrP C ) plays a fundamental role in prion disease. PrP C is a glycosylphosphatidylinositol (GPI)-anchored protein with two variably occupied N-glycosylation sites. In general, GPI-anchor and N-glycosylation direct proteins to apical membranes in polarized cells whereas the majority of mouse PrP C is found in basolateral membranes in polarized Madin-Darby canine kidney (MDCK) cells. In this study we have mutated the first, the second, and both N-glycosylation sites of PrP C and also replaced the GPI-anchor of PrP C by the Thy-1 GPI-anchor in order to investigate the role of these signals in sorting of PrP C in MDCK cells. Cell surface biotinylation experiments and confocal microscopy showed that lack of one N-linked oligosaccharide leads to loss of polarized sorting of PrP C . Exchange of the PrP C GPI-anchor for the one of Thy-1 redirects PrP C to the apical membrane. In conclusion, both N-glycosylation and GPI-anchor act on polarized sorting of PrP C , with the GPI-anchor being dominant over N-glycans.
    Keywords: Research Article ; Biology ; Medicine ; Veterinary Science ; Infectious Diseases ; Cell Biology ; Physiology ; Neuroscience
    E-ISSN: 1932-6203
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  • 3
    Language: English
    In: PLoS ONE, 2011, Vol.6(5), p.e19121
    Description: Chemotherapy of glioblastoma is largely ineffective as the blood-brain barrier (BBB) prevents entry of most anticancer agents into the brain. For an efficient treatment of glioblastomas it is necessary to deliver anti-cancer drugs across the intact BBB. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles coated with poloxamer 188 hold great promise as drug carriers for brain delivery after their intravenous injection. In the present study the anti-tumour efficacy of the surfactant-coated doxorubicin-loaded PLGA nanoparticles against rat glioblastoma 101/8 was investigated using histological and immunohistochemical methods. ; The particles were prepared by a high-pressure solvent evaporation technique using 1% polyvinylalcohol (PLGA/PVA) or human serum albumin (PLGA/HSA) as stabilizers. Additionally, lecithin-containing PLGA/HSA particles (Dox-Lecithin-PLGA/HSA) were prepared. For evaluation of the antitumour efficacy the glioblastoma-bearing rats were treated intravenously with the doxorubicin-loaded nanoparticles coated with poloxamer 188 using the following treatment regimen: 3×2.5 mg/kg on day 2, 5 and 8 after tumour implantation; doxorubicin and poloxamer 188 solutions were used as controls. On day 18, the rats were sacrificed and the antitumour effect was determined by measurement of tumour size, necrotic areas, proliferation index, and expression of GFAP and VEGF as well as Isolectin B4, a marker for the vessel density. ; The results reveal a considerable anti-tumour effect of the doxorubicin-loaded nanoparticles. The overall best results were observed for Dox-Lecithin-PLGA/HSA. These data demonstrate that the poloxamer 188-coated PLGA nanoparticles enable delivery of doxorubicin across the blood-brain barrier in the therapeutically effective concentrations.
    Keywords: Research Article ; Biology ; Medicine ; Immunology ; Oncology
    E-ISSN: 1932-6203
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  • 4
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 28 October 2014, Vol.111(43), pp.15573-15578
    Description: Mutations within the lysosomal enzyme β-glucocerebrosidase (GC) result in Gaucher disease and represent a major risk factor for developing Parkinson disease (PD). Loss of GC activity leads to accumulation of its substrate glucosylceramide and α-synuclein. Since lysosomal activity of GC is tightly linked to expression of its trafficking receptor, the lysosomal integral membrane protein type-2 (LIMP-2), we studied á-synuclein metabolism in LIMP-2-deficient mice. These mice showed an α-synuclein dosage-dependent phenotype, including severe neurological impairments and premature death. In LIMP-2-deficient brains a significant reduction in GC activity led to lipid storage, disturbed autophagic/lysosomal function, and α-synuclein accumulation mediating neurotoxicity of dopaminergic (DA) neurons, apoptotic cell death, and inflammation. Heterologous expression of LIMP-2 accelerated clearance of overexpressed α-synuclein, possibly through increasing lysosomal GC activity. In surviving DA neurons of human PD midbrain, LIMP-2 levels were increased, probably to compensate for lysosomal GC deficiency. Therefore, we suggest that manipulating LIMP-2 expression to increase lysosomal GC activity is a promising strategy for the treatment of synucleinopathies.
    Keywords: Biological sciences -- Biology -- Cytology ; Biological sciences -- Biology -- Anatomy ; Biological sciences -- Biology -- Anatomy ; Health sciences -- Medical conditions -- Diseases ; Health sciences -- Medical conditions -- Diseases ; Biological sciences -- Biology -- Genetics ; Biological sciences -- Biology -- Zoology ; Physical sciences -- Astronomy -- Astronomical objects ; Health sciences -- Medical sciences -- Immunology ; Biological sciences -- Biochemistry -- Biomolecules
    ISSN: 00278424
    E-ISSN: 10916490
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  • 5
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 28 October 2014, Vol.111(43), pp.15573-8
    Description: Mutations within the lysosomal enzyme β-glucocerebrosidase (GC) result in Gaucher disease and represent a major risk factor for developing Parkinson disease (PD). Loss of GC activity leads to accumulation of its substrate glucosylceramide and α-synuclein. Since lysosomal activity of GC is tightly linked to expression of its trafficking receptor, the lysosomal integral membrane protein type-2 (LIMP-2), we studied α-synuclein metabolism in LIMP-2-deficient mice. These mice showed an α-synuclein dosage-dependent phenotype, including severe neurological impairments and premature death. In LIMP-2-deficient brains a significant reduction in GC activity led to lipid storage, disturbed autophagic/lysosomal function, and α-synuclein accumulation mediating neurotoxicity of dopaminergic (DA) neurons, apoptotic cell death, and inflammation. Heterologous expression of LIMP-2 accelerated clearance of overexpressed α-synuclein, possibly through increasing lysosomal GC activity. In surviving DA neurons of human PD midbrain, LIMP-2 levels were increased, probably to compensate for lysosomal GC deficiency. Therefore, we suggest that manipulating LIMP-2 expression to increase lysosomal GC activity is a promising strategy for the treatment of synucleinopathies.
    Keywords: Amrf ; C57/Bl6-J ; Gd ; Pme ; Scarb2 ; Glucosylceramidase -- Metabolism ; Lysosome-Associated Membrane Glycoproteins -- Metabolism ; Alpha-Synuclein -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 6
    Language: English
    In: PLoS ONE, 01 January 2013, Vol.8(12), p.e82255
    Description: Alzheimer's disease (AD) is the most common form of dementia in the elderly with progressive cognitive decline and memory loss. According to the amyloid-hypothesis, AD is caused by generation and subsequent cerebral deposition of β-amyloid (Aβ). Aβ is generated through sequential cleavage of the transmembrane Amyloid-Precursor-Protein (APP) by two endoproteinases termed beta- and gamma-secretase. Increased APP-expression caused by APP gene dosage effects is a risk factor for the development of AD. Here we carried out a large scale screen for novel compounds aimed at decreasing APP-expression. For this we developed a screening system employing a cell culture model of AD. A total of 10,000 substances selected for their ability of drug-likeness and chemical diversity were tested for their potential to decrease APP-expression resulting in reduced Aβ-levels. Positive compounds were further evaluated for their effect at lower concentrations, absence of cytotoxicity and specificity. The six most promising compounds were characterized and structure function relationships were established. The novel compounds presented here provide valuable information for the development of causal therapies for AD.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 7
    In: Brain Pathology, January 2017, Vol.27(1), pp.107-108
    Description: This commentary highlights the study by Frau‐Mendez and coworkers in this issue of (xxx) in which the authors show evidence for involvement of mitochondria in the pathophysiology of fatal familial insomnia (FFI). Using genetic, biochemical and morphological means, they provide a comprehensive picture of the degree of mitochondrial damage in FFI and show that this leads to increased oxidative stress. This adds FFI to the growing list of dementias with mitochondrial involvement. Future studies will have to address the causality dilemma of which came first, mitochondrial damage and subsequent neurodegeneration or vice versa. Either way, these data provide the basis to devise novel therapeutic strategies for FFI.
    Keywords: Prion Diseases – Genetic Aspects ; Insomnia – Genetic Aspects;
    ISSN: 1015-6305
    E-ISSN: 1750-3639
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  • 8
    Language: English
    In: PLoS ONE, 01 January 2013, Vol.8(5), p.e63118
    Description: The only approved pharmacological treatment for ischemic stroke is intravenous administration of plasminogen activator (tPA) to re-canalize the occluded cerebral vessel. Not only reperfusion but also tPA itself can induce an inflammatory response. Microglia are the innate immune cells of the central nervous system and the first immune cells to become activated in stroke. Neuroserpin, an endogenous inhibitor of tPA, is up-regulated following cerebral ischemia. To examine neuroserpin-dependent mechanisms of neuroprotection in stroke, we studied neuroserpin deficient (Ns(-/-))mice in an animal model of temporal focal ischemic stroke. Infarct size and neurological outcome were worse in neuroserpin deficient mice even though the fibrinolytic activity in the ischemic brain was increased. The increased infarct size was paralleled by a selective increase in proinflammatory microglia activation in Ns(-/-) mice. Our results show excessive microglial activation in Ns(-/-) mice mediated by an increased activity of tPA. This activation results in a worse outcome further underscoring the potential detrimental proinflammatory effects of tPA.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 9
    Language: English
    In: Analytical chemistry, 03 July 2018, Vol.90(13), pp.7871-7879
    Description: Cells release vesicles to the surroundings, the extracellular vesicles (EVs), which may transmit biomolecules to other cells, and are found in bodily fluids, thus constituting emerging biomarker targets. Many studies on EV nucleic acid, lipid, and protein composition are available; however, detailed characterization of protein glycosylation has been less approached. Here, we describe a strategy for high-resolution quantitative profiling and structure elucidation of N-glycans from EV glycoproteins of three cell lines: human HEK-293, human glioma H4 and mouse glioma Tu-2449. EVs have been purified from cell supernatants by ultracentrifugation and compared with total cellular membranes (CMs). CMs and EVs have been characterized by immunoblotting using a panel of EV-specific antibodies, electron microscopy, and immunocytochemistry. N-Glycans were released from membrane-derived tryptic glycopeptides with peptide N-glycosidase F, labeled with 2-aminobenzamide and analyzed by normal phase-high-pressure liquid chromatography (NP-HPLC) and matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF) mass spectrometry. For the three cell lines, enrichment in complex N-glycans was found in EVs concomitant to a small amount of high mannose glycans, whereas CMs were highly enriched in high mannose glycans. In HEK-293 and H4 EVs, the predominant N-glycan was tetraantennary proximally fucosylated with α2,3-linked N-acetylneuraminic acid; HEK-293 EVs also contained the LacdiNAc structure. Mouse Tu-2449 EV profiles were very heterogeneous, with di-, tri-, and tetraantennary proximally fucosylated glycans and the presence of peripheral Galα3Gal structure. The results opened novel perspectives to further investigate the roles of glycans in EVs biological properties and may contribute to the biomarker field in glioma.
    Keywords: Glycosylation ; Cells ; Brain Cancer ; Mass Spectrometry ; Vesicles ; Glycopeptides ; Proteins ; Antibodies ; Body Fluids ; Ionization ; Biomarkers ; Biological Properties ; High Performance Liquid Chromatography ; Glycan ; Mannose ; Biotechnology ; Biomolecules ; Nucleic Acids;
    ISSN: 00032700
    E-ISSN: 1520-6882
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  • 10
    In: Nature, 2013, Vol.495(7442), p.474
    Description: CLP1 was the first mammalian RNA kinase to be identified. However, determining its in vivo function has been elusive. Here we generated kinase-dead Clp1 (Clp1K/K) mice that show a progressive loss of spinal motor neurons associated with axonal degeneration in the peripheral nerves and denervation of neuromuscular junctions, resulting in impaired motor function, muscle weakness, paralysis and fatal respiratory failure. Transgenic rescue experiments show that CLP1 functions in motor neurons. Mechanistically, loss of CLP1 activity results in accumulation of a novel set of small RNA fragments, derived from aberrant processing of tyrosine pre-transfer RNA. These tRNA fragments sensitize cells to oxidative-stress-induced p53 (also known as TRP53) activation and p53-dependent cell death. Genetic inactivation of p53 rescues Clp1K/K mice from the motor neuron loss, muscle denervation and respiratory failure. Our experiments uncover a mechanistic link between tRNA processing, formation of a new RNA species and progressive loss of lower motor neurons regulated by p53. [PUBLICATION ]
    Keywords: Amyotrophic Lateral Sclerosis–Metabolism ; Animals–Pathology ; Animals, Newborn–Innervation ; Axons–Metabolism ; Axons–Pathology ; Cell Death–Genetics ; Diaphragm–Metabolism ; Embryo Loss–Pathology ; Embryo, Mammalian–Metabolism ; Embryo, Mammalian–Pathology ; Exons–Genetics ; Female–Metabolism ; Fibroblasts–Cytology ; Male–Deficiency ; Mice–Metabolism ; Mice, Inbred C57bl–Metabolism ; Mice, Knockout–Genetics ; Mice, Transgenic–Metabolism ; Motor Neurons–Metabolism ; Motor Neurons–Metabolism ; Muscular Atrophy, Spinal–Metabolism ; Neuromuscular Diseases–Metabolism ; Neuromuscular Diseases–Metabolism ; Oxidative Stress–Metabolism ; RNA Processing, Post-Transcriptional–Metabolism ; RNA, Transfer, Tyr–Metabolism ; RNA, Transfer, Tyr–Metabolism ; Respiration–Metabolism ; Spinal Nerves–Metabolism ; Transcription Factors–Metabolism ; Transcription Factors–Metabolism ; Tumor Suppressor Protein P53–Metabolism ; Tyrosine–Metabolism ; Tyrosine–Metabolism ; Neurons ; Proteins ; Mutation ; Rodents ; Kinases ; Hexim1 Protein, Mouse ; RNA, Transfer, Tyr ; Transcription Factors ; Tumor Suppressor Protein P53 ; Tyrosine;
    ISSN: 0028-0836
    E-ISSN: 14764687
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