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Berlin Brandenburg

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  • 1
    Language: English
    In: Science (New York, N.Y.), 18 January 2019, Vol.363(6424), pp.207
    Description: A vocal minority in the United States is intent on stopping federal funding for research using human fetal tissue, citing stem cell–based or other alternatives as adequate. This view is scientifically inaccurate. It ignores the current limitations of stem cell research and disregards the value of fetal...
    Keywords: Congenital Defects ; Cancer ; Tissues ; Infectious Diseases ; Heart Diseases ; Infectious Diseases ; Stem Cells ; Stem Cells ; Stem Cells ; Congenital Defects ; Cancer ; Heart Diseases ; Birth Defects ; Infectious Diseases ; Fetuses ; Coronary Artery Disease;
    ISSN: 00368075
    E-ISSN: 1095-9203
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  • 2
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 29 May 2012, Vol.109(22), pp.8582-7
    Description: Intracellular transport of vesicles and organelles along microtubules is powered by kinesin and cytoplasmic dynein molecular motors. Both motors can attach to the same cargo and thus must be coordinated to ensure proper distribution of intracellular materials. Although a number of hypotheses have been proposed to explain how these motors are coordinated, considerable uncertainty remains, in part because of the absence of methods for assessing motor subunit composition on individual vesicular cargos. We developed a robust quantitative immunofluorescence method based on subpixel colocalization to elucidate relative kinesin-1 and cytoplasmic dynein motor subunit composition of individual, endogenous amyloid precursor protein (APP) vesicles in mouse hippocampal cells. The resulting method and data allow us to test a key in vivo prediction of the hypothesis that APP can recruit kinesin-1 to APP vesicles in neuronal axons. We found that APP levels are well-correlated with the amount of the light chain of kinesin-1 (KLC1) and the heavy chain of cytoplasmic dynein (DHC1) on vesicles. In addition, genetic reduction of APP diminishes KLC1 and DHC1 levels on APP cargos. Finally, our data reveal that reduction of KLC1 leads to decreased levels of DHC1 on APP vesicles, suggesting that KLC1 is necessary for the association of DHC1 to these cargos, and help to explain previously reported retrograde transport defects generated when kinesin-1 is reduced.
    Keywords: Amyloid Beta-Protein Precursor -- Metabolism ; Cytoplasmic Dyneins -- Metabolism ; Cytoplasmic Vesicles -- Metabolism ; Microtubule-Associated Proteins -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 3
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 2012, Vol.109(22), pp.8582-8587
    Description: Intracellular transport of vesicles and organelles along microtubules is powered by kinesin and cytoplasmic dynein molecular motors. Both motors can attach to the same cargo and thus must be coordinated to ensure proper distribution of intracellular materials. Although a number of hypotheses have been proposed to explain how these motors are coordinated, considerable uncertainty remains, in part because of the absence of methods for assessing motor subunit composition on individual vesicular cargos. We developed a robust quantitative immunofluorescence method based on subpixel colocalization to elucidate relative kinesin-1 and cytoplasmic dynein motor subunit composition of individual, endogenous amyloid precursor protein (APP) vesicles in mouse hippocampal cells. The resulting method and data allow us to test a key in vivo prediction of the hypothesis that APP can recruit kinesin-1 to APP vesicles in neuronal axons. We found that APP levels are well-correlated with the amount of the light chain of kinesin-1 (KLC1) and the heavy chain of cytoplasmic dynein (DHC1) on vesicles. In addition, genetic reduction of APP diminishes KLC1 and DHC1 levels on APP cargos. Finally, our data reveal that reduction of KLC1 leads to decreased levels of DHC1 on APP vesicles, suggesting that KLC1 is necessary for the association of DHC1 to these cargos, and help to explain previously reported retrograde transport defects generated when kinesin-1 is reduced. ; p. 8582-8587.
    Keywords: Mice ; Microtubules ; Axons ; Organelles ; Prediction ; Fluorescent Antibody Technique ; Dynein Atpase ; Amyloid ; Uncertainty
    ISSN: 0027-8424
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  • 4
    In: Science, March 16, 2001, Vol.291(5511), p.2102
    Keywords: Transport Proteins -- Research ; Cell Transplantation
    ISSN: 0036-8075
    E-ISSN: 10959203
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  • 5
    Language: English
    In: PLoS ONE, 2012, Vol.7(1), p.e29755
    Description: The etiology of sporadic Alzheimer disease (AD) is largely unknown, although evidence implicates the pathological hallmark molecules amyloid beta (Aβ) and phosphorylated Tau. Work in animal models suggests that altered axonal transport caused by Kinesin-1 dysfunction perturbs levels of both Aβ and phosphorylated Tau in neural tissues, but the relevance of Kinesin-1 dependent functions to the human disease is unknown. To begin to address this issue, we generated human embryonic stem cells (hESC) expressing reduced levels of the kinesin light chain 1 (KLC1) Kinesin-1 subunit to use as a source of human neural cultures. Despite reduction of KLC1, undifferentiated hESC exhibited apparently normal colony morphology and pluripotency marker expression. Differentiated neural cultures derived from KLC1-suppressed hESC contained neural rosettes but further differentiation revealed obvious morphological changes along with reduced levels of microtubule-associated neural proteins, including Tau and less secreted Aβ, supporting the previously established connection between KLC1, Tau and Aβ. Intriguingly, KLC1-suppressed neural precursors (NPs), isolated using a cell surface marker signature known to identify cells that give rise to neurons and glia, unlike control cells, failed to proliferate. We suggest that KLC1 is required for normal human neural differentiation, ensuring proper metabolism of AD-associated molecules APP and Tau and for proliferation of NPs. Because impaired APP metabolism is linked to AD, this human cell culture model system will not only be a useful tool for understanding the role of KLC1 in regulating the production, transport and turnover of APP and Tau in neurons, but also in defining the essential function(s) of KLC1 in NPs and their progeny. This knowledge should have important implications for human neurodevelopmental and neurodegenerative diseases.
    Keywords: Research Article ; Biology ; Cell Biology ; Neuroscience ; Developmental Biology
    E-ISSN: 1932-6203
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  • 6
    In: Proceedings of the National Academy of Sciences of the United States, June 19, 2001, Vol.98(13), p.6999
    Description: Kinesin molecular motor proteins are responsible for many of the major microtubule-dependent transport pathways in neuronal and non-neuronal cells. Elucidating the transport pathways mediated by kinesins, the identity of the cargoes moved, and the nature of the proteins that link kinesin motors to cargoes are areas of intense investigation. Kinesin-II recently was found to be required for transport in motile and nonmotile cilia and flagella where it is essential for proper left-right determination in mammalian development, sensory function in ciliated neurons, and opsin transport and viability in photoreceptors. Thus, these pathways and proteins may be prominent contributors to several human diseases including ciliary dyskinesias, situs inversus, and retinitis pigmentosa. Kinesin-I is needed to move many different types of cargoes in neuronal axons. Two candidates for receptor proteins that attach kinesin-I to vesicular cargoes were recently found. One candidate, sunday driver, is proposed to both link kinesin-I to an unknown vesicular cargo and to bind and organize the mitogen-activated protein kinase components of a c-Jun N-terminal kinase signaling module. A second candidate, amyloid precursor protein, is proposed to link kinesin-I to a different, also unknown, class of axonal vesicles. The finding of a possible functional interaction between kinesin-I and amyloid precursor protein may implicate kinesin-I based transport in the development of Alzheimer's disease.
    Keywords: Kinesin -- Physiological Aspects ; Biological Transport -- Research
    ISSN: 0027-8424
    E-ISSN: 10916490
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  • 7
    Language: English
    In: PLoS ONE, 01 January 2013, Vol.8(6), p.e68324
    Description: Axonal transport, a form of long-distance, bi-directional intracellular transport that occurs between the cell body and synaptic terminal, is critical in maintaining the function and viability of neurons. We have identified a requirement for the stathmin (stai) gene in the maintenance of axonal...
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 8
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 15 February 2011, Vol.108(7), pp.3005-10
    Description: A major goal of stem-cell research is to identify conditions that reliably regulate their differentiation into specific cell types. This goal is particularly important for human stem cells if they are to be used for in vivo transplantation or as a platform for drug development. Here we describe the establishment of procedures to direct the differentiation of human embryonic stem cells and human induced pluripotent stem cells into forebrain neurons that are capable of forming synaptic connections. In addition, HEK293T cells expressing Neuroligin (NLGN) 3 and NLGN4, but not those containing autism-associated mutations, are able to induce presynaptic differentiation in human induced pluripotent stem cell-derived neurons. We show that a mutant NLGN4 containing an in-frame deletion is unable to localize correctly to the cell surface when overexpressed and fails to enhance synapse formation in human induced pluripotent stem cell-derived neurons. These findings establish human pluripotent stem cell-derived neurons as a viable model for the study of synaptic differentiation and function under normal and disorder-associated conditions.
    Keywords: Cell Differentiation -- Physiology ; Child Development Disorders, Pervasive -- Genetics ; Embryonic Stem Cells -- Cytology ; Neurons -- Cytology ; Pluripotent Stem Cells -- Cytology ; Prosencephalon -- Cytology ; Synapses -- Physiology
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 9
    Language: English
    In: The Journal of biological chemistry, 20 July 2018, Vol.293(29), pp.11341-11357
    Description: Mounting evidence suggests that alterations in cholesterol homeostasis are involved in Alzheimer's disease (AD) pathogenesis. Amyloid precursor protein (APP) or multiple fragments generated by proteolytic processing of APP have previously been implicated in the regulation of cholesterol metabolism. However, the physiological function of APP in regulating lipoprotein homeostasis in astrocytes, which are responsible for cholesterol biosynthesis and regulation in the brain, remains unclear. To address this, here we used CRISPR/Cas9 genome editing to generate isogenic APP-knockout (KO) human induced pluripotent stem cells (hiPSCs) and differentiated them into human astrocytes. We found that APP-KO astrocytes have reduced cholesterol and elevated levels of sterol regulatory element-binding protein (SREBP) target gene transcripts and proteins, which were both downstream consequences of reduced lipoprotein endocytosis. To elucidate which APP fragments regulate cholesterol homeostasis and to examine whether familial AD mutations in APP affect lipoprotein metabolism, we analyzed an isogenic allelic series harboring the APP Swedish and APP V717F variants. Only astrocytes homozygous for the APP Swedish (APP) mutation, which had reduced full-length APP (FL APP) due to increased β-secretase cleavage, recapitulated the APP-KO phenotypes. Astrocytic internalization of β-amyloid (Aβ), another ligand for low-density lipoprotein (LDL) receptors, was also impaired in APP-KO and APP astrocytes. Finally, impairing cleavage of FL APP through β-secretase inhibition in APP astrocytes reversed the LDL and Aβ endocytosis defects. In conclusion, FL APP is involved in the endocytosis of LDL receptor ligands and is required for proper cholesterol homeostasis and Aβ clearance in human astrocytes.
    Keywords: Alzheimer Disease ; Amyloid Precursor Protein (App) ; Amyloid-Beta (Aβ) ; Astrocyte ; Cholesterol Metabolism ; Induced Pluripotent Stem Cell (Ips Cell) (Ipsc) ; Lipoprotein Metabolism ; Lipoprotein Receptor ; Amyloid Beta-Peptides -- Metabolism ; Amyloid Beta-Protein Precursor -- Metabolism ; Astrocytes -- Metabolism ; Cholesterol -- Metabolism ; Lipoproteins -- Metabolism
    ISSN: 00219258
    E-ISSN: 1083-351X
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  • 10
    Language: English
    In: Molecular biology of the cell, September 2012, Vol.23(17), pp.3279-80
    Description: The American Society for Cell Biology is targeting the first week of October 2012 (the week before Nobel Prize winners are announced) to launch the We Are Research initiative. The goal of this initiative is to mobilize practicing junior and senior scientists, including graduate students, postdocs, and other lab members, to make contact with their elected officials and neighbors and explain to them why Federal support and investment in biomedical research is vital to the health and economic welfare of the United States. This initiative is designed to illustrate how important people are to scientific research and to supply our representatives with reliable and accurate information in the form of letters, emails, telephone calls, and personal visits.
    Keywords: Biomedical Research ; Lobbying ; Research Support As Topic ; Societies, Scientific
    ISSN: 10591524
    E-ISSN: 1939-4586
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