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  • 1
    Publication Date: 2013-11-02
    Description: We used single-cell genomic approaches to map DNA copy number variation (CNV) in neurons obtained from human induced pluripotent stem cell (hiPSC) lines and postmortem human brains. We identified aneuploid neurons, as well as numerous subchromosomal CNVs in euploid neurons. Neurotypic hiPSC-derived neurons had larger CNVs than fibroblasts, and several large deletions were found in hiPSC-derived neurons but not in matched neural progenitor cells. Single-cell sequencing of endogenous human frontal cortex neurons revealed that 13 to 41% of neurons have at least one megabase-scale de novo CNV, that deletions are twice as common as duplications, and that a subset of neurons have highly aberrant genomes marked by multiple alterations. Our results show that mosaic CNV is abundant in human neurons.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3975283/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3975283/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McConnell, Michael J -- Lindberg, Michael R -- Brennand, Kristen J -- Piper, Julia C -- Voet, Thierry -- Cowing-Zitron, Chris -- Shumilina, Svetlana -- Lasken, Roger S -- Vermeesch, Joris R -- Hall, Ira M -- Gage, Fred H -- DP2 OD006493/OD/NIH HHS/ -- DP20D006493-01/DP/NCCDPHP CDC HHS/ -- HHSN2752009000011C/PHS HHS/ -- N01-HD-9-011/HD/NICHD NIH HHS/ -- R01 MH095741/MH/NIMH NIH HHS/ -- New York, N.Y. -- Science. 2013 Nov 1;342(6158):632-7. doi: 10.1126/science.1243472.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24179226" target="_blank"〉PubMed〈/a〉
    Keywords: Aneuploidy ; *DNA Copy Number Variations ; Frontal Lobe/*cytology ; Humans ; Induced Pluripotent Stem Cells/cytology ; Male ; *Mosaicism ; Neural Stem Cells/*cytology ; Neurogenesis ; Neurons/*cytology ; Sequence Analysis, DNA ; Sequence Deletion ; Single-Cell Analysis
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2012-03-30
    Description: Glial cells constitute nearly 50% of the cells in the human brain. Astrocytes, which make up the largest glial population, are crucial to the regulation of synaptic connectivity during postnatal development. Because defects in astrocyte generation are associated with severe neurological disorders such as brain tumours, it is important to understand how astrocytes are produced. Astrocytes reportedly arise from two sources: radial glia in the ventricular zone and progenitors in the subventricular zone, with the contribution from each region shifting with time. During the first three weeks of postnatal development, the glial cell population, which contains predominantly astrocytes, expands 6-8-fold in the rodent brain. Little is known about the mechanisms underlying this expansion. Here we show that a major source of glia in the postnatal cortex in mice is the local proliferation of differentiated astrocytes. Unlike glial progenitors in the subventricular zone, differentiated astrocytes undergo symmetric division, and their progeny integrate functionally into the existing glial network as mature astrocytes that form endfeet with blood vessels, couple electrically to neighbouring astrocytes, and take up glutamate after neuronal activity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3777276/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3777276/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ge, Woo-Ping -- Miyawaki, Atsushi -- Gage, Fred H -- Jan, Yuh Nung -- Jan, Lily Yeh -- 1K99NS073735/NS/NINDS NIH HHS/ -- 4R37MH065334/MH/NIMH NIH HHS/ -- MH090258/MH/NIMH NIH HHS/ -- P01 AG010435/AG/NIA NIH HHS/ -- R01 MH090258/MH/NIMH NIH HHS/ -- R37 MH065334/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Mar 28;484(7394):376-80. doi: 10.1038/nature10959.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Department of Physiology, University of California at San Francisco, 1550 4th Street, San Francisco, California 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22456708" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Animals, Newborn ; Astrocytes/*cytology/metabolism/physiology ; Cell Differentiation ; Cell Division ; *Cell Lineage ; Cell Proliferation ; Cerebral Cortex/*cytology ; Glutamic Acid/metabolism ; Mice ; Mice, Transgenic ; Neuroglia/*cytology/metabolism ; Time-Lapse Imaging
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2012-09-14
    Description: Embryonic stem cells can replicate continuously in the absence of senescence and, therefore, are immortal in culture. Although genome stability is essential for the survival of stem cells, proteome stability may have an equally important role in stem-cell identity and function. Furthermore, with the asymmetric divisions invoked by stem cells, the passage of damaged proteins to daughter cells could potentially destroy the resulting lineage of cells. Therefore, a firm understanding of how stem cells maintain their proteome is of central importance. Here we show that human embryonic stem cells (hESCs) exhibit high proteasome activity that is correlated with increased levels of the 19S proteasome subunit PSMD11 (known as RPN-6 in Caenorhabditis elegans) and a corresponding increased assembly of the 26S/30S proteasome. Ectopic expression of PSMD11 is sufficient to increase proteasome assembly and activity. FOXO4, an insulin/insulin-like growth factor-I (IGF-I) responsive transcription factor associated with long lifespan in invertebrates, regulates proteasome activity by modulating the expression of PSMD11 in hESCs. Proteasome inhibition in hESCs affects the expression of pluripotency markers and the levels of specific markers of the distinct germ layers. Our results suggest a new regulation of proteostasis in hESCs that links longevity and stress resistance in invertebrates to hESC function and identity.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vilchez, David -- Boyer, Leah -- Morantte, Ianessa -- Lutz, Margaret -- Merkwirth, Carsten -- Joyce, Derek -- Spencer, Brian -- Page, Lesley -- Masliah, Eliezer -- Berggren, W Travis -- Gage, Fred H -- Dillin, Andrew -- R37 AG018440/AG/NIA NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Sep 13;489(7415):304-8. doi: 10.1038/nature11468.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Glenn Center for Aging Research, Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22972301" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Differentiation ; Cell Line ; Embryonic Stem Cells/drug effects/*enzymology/metabolism ; HEK293 Cells ; Humans ; Pluripotent Stem Cells/cytology/metabolism ; Proteasome Endopeptidase Complex/*metabolism ; Proteasome Inhibitors ; Protein Subunits/metabolism ; Transcription Factors/metabolism ; Up-Regulation
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2015-11-03
    Description: Bipolar disorder is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression; without treatment, 15% of patients commit suicide. Hence, it has been ranked by the World Health Organization as a top disorder of morbidity and lost productivity. Previous neuropathological studies have revealed a series of alterations in the brains of patients with bipolar disorder or animal models, such as reduced glial cell number in the prefrontal cortex of patients, upregulated activities of the protein kinase A and C pathways and changes in neurotransmission. However, the roles and causation of these changes in bipolar disorder have been too complex to exactly determine the pathology of the disease. Furthermore, although some patients show remarkable improvement with lithium treatment for yet unknown reasons, others are refractory to lithium treatment. Therefore, developing an accurate and powerful biological model for bipolar disorder has been a challenge. The introduction of induced pluripotent stem-cell (iPSC) technology has provided a new approach. Here we have developed an iPSC model for human bipolar disorder and investigated the cellular phenotypes of hippocampal dentate gyrus-like neurons derived from iPSCs of patients with bipolar disorder. Guided by RNA sequencing expression profiling, we have detected mitochondrial abnormalities in young neurons from patients with bipolar disorder by using mitochondrial assays; in addition, using both patch-clamp recording and somatic Ca(2+) imaging, we have observed hyperactive action-potential firing. This hyperexcitability phenotype of young neurons in bipolar disorder was selectively reversed by lithium treatment only in neurons derived from patients who also responded to lithium treatment. Therefore, hyperexcitability is one early endophenotype of bipolar disorder, and our model of iPSCs in this disease might be useful in developing new therapies and drugs aimed at its clinical treatment.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742055/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742055/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mertens, Jerome -- Wang, Qiu-Wen -- Kim, Yongsung -- Yu, Diana X -- Pham, Son -- Yang, Bo -- Zheng, Yi -- Diffenderfer, Kenneth E -- Zhang, Jian -- Soltani, Sheila -- Eames, Tameji -- Schafer, Simon T -- Boyer, Leah -- Marchetto, Maria C -- Nurnberger, John I -- Calabrese, Joseph R -- Odegaard, Ketil J -- McCarthy, Michael J -- Zandi, Peter P -- Alda, Martin -- Nievergelt, Caroline M -- Pharmacogenomics of Bipolar Disorder Study -- Mi, Shuangli -- Brennand, Kristen J -- Kelsoe, John R -- Gage, Fred H -- Yao, Jun -- MH106056/MH/NIMH NIH HHS/ -- R01 MH106056/MH/NIMH NIH HHS/ -- U01 MH092758/MH/NIMH NIH HHS/ -- U01 MH92758/MH/NIMH NIH HHS/ -- England -- Nature. 2015 Nov 5;527(7576):95-9. doi: 10.1038/nature15526. Epub 2015 Oct 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Membrane Biology, Tsinghua-Peking Joint Center for Life Sciences, McGovern Institute for Brain Research, School of Life Sciences, Tsinghua University, Beijing 100084, China. ; The Salk Institute for Biological Studies, Laboratory of Genetics, La Jolla, California 92037, USA. ; The Salk Institute for Biological Studies, Stem Cell Core, La Jolla, California 92037, USA. ; Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China. ; Department of Psychiatry, Indiana University, Indianapolis, Indiana 46202, USA. ; Department of Psychiatry, Case Western Reserve University, Cleveland, Ohio 44106, USA. ; Department of Psychiatry, University of Bergen, Bergen 5020, Norway. ; Department of Psychiatry, VA San Diego Healthcare System, La Jolla, California 92151, USA. ; Department of Psychiatry, University of California San Diego, La Jolla, California, 92093, USA. ; Department of Psychiatry, Johns Hopkins University, Baltimore, Maryland 21218, USA. ; Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, B3H2E2, Canada. ; Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029, USA. ; Jiangsu Collaborative Innovation Center for Language Ability, Jiangsu Normal University, Xuzhou 221009, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26524527" target="_blank"〉PubMed〈/a〉
    Keywords: Action Potentials/*drug effects ; Antipsychotic Agents/*pharmacology ; Bipolar Disorder/*pathology ; Calcium Signaling/drug effects ; Dentate Gyrus/drug effects/pathology ; Endophenotypes ; Humans ; Induced Pluripotent Stem Cells/pathology ; Lithium Compounds/*pharmacology ; Male ; Mitochondria/pathology ; Neurons/*drug effects/*pathology ; Patch-Clamp Techniques
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2013-10-25
    Description: Identifying cellular and molecular differences between human and non-human primates (NHPs) is essential to the basic understanding of the evolution and diversity of our own species. Until now, preserved tissues have been the main source for most comparative studies between humans, chimpanzees (Pan troglodytes) and bonobos (Pan paniscus). However, these tissue samples do not fairly represent the distinctive traits of live cell behaviour and are not amenable to genetic manipulation. We propose that induced pluripotent stem (iPS) cells could be a unique biological resource to determine relevant phenotypical differences between human and NHPs, and that those differences could have potential adaptation and speciation value. Here we describe the generation and initial characterization of iPS cells from chimpanzees and bonobos as new tools to explore factors that may have contributed to great ape evolution. Comparative gene expression analysis of human and NHP iPS cells revealed differences in the regulation of long interspersed element-1 (L1, also known as LINE-1) transposons. A force of change in mammalian evolution, L1 elements are retrotransposons that have remained active during primate evolution. Decreased levels of L1-restricting factors APOBEC3B (also known as A3B) and PIWIL2 (ref. 7) in NHP iPS cells correlated with increased L1 mobility and endogenous L1 messenger RNA levels. Moreover, results from the manipulation of A3B and PIWIL2 levels in iPS cells supported a causal inverse relationship between levels of these proteins and L1 retrotransposition. Finally, we found increased copy numbers of species-specific L1 elements in the genome of chimpanzees compared to humans, supporting the idea that increased L1 mobility in NHPs is not limited to iPS cells in culture and may have also occurred in the germ line or embryonic cells developmentally upstream to germline specification during primate evolution. We propose that differences in L1 mobility may have differentially shaped the genomes of humans and NHPs and could have continuing adaptive significance.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4064720/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4064720/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Marchetto, Maria C N -- Narvaiza, Inigo -- Denli, Ahmet M -- Benner, Christopher -- Lazzarini, Thomas A -- Nathanson, Jason L -- Paquola, Apua C M -- Desai, Keval N -- Herai, Roberto H -- Weitzman, Matthew D -- Yeo, Gene W -- Muotri, Alysson R -- Gage, Fred H -- AI074967/AI/NIAID NIH HHS/ -- GM084317/GM/NIGMS NIH HHS/ -- HG004659/HG/NHGRI NIH HHS/ -- MH08848/MH/NIMH NIH HHS/ -- MH094753/MH/NIMH NIH HHS/ -- NS075449/NS/NINDS NIH HHS/ -- P30 CA014195/CA/NCI NIH HHS/ -- R01 MH088485/MH/NIMH NIH HHS/ -- R01 MH094753/MH/NIMH NIH HHS/ -- R01 MH095741/MH/NIMH NIH HHS/ -- R01 NS075449/NS/NINDS NIH HHS/ -- England -- Nature. 2013 Nov 28;503(7477):525-9. doi: 10.1038/nature12686. Epub 2013 Oct 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA [2].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24153179" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Argonaute Proteins/metabolism ; Cell Line ; Cell Shape ; Cytidine Deaminase/metabolism ; Evolution, Molecular ; Genome, Human/genetics ; High-Throughput Nucleotide Sequencing ; Humans ; Karyotyping ; Long Interspersed Nucleotide Elements/*genetics ; Mice, Nude ; Pan paniscus/*genetics/metabolism ; Pan troglodytes/*genetics/metabolism ; Pluripotent Stem Cells/cytology/*metabolism ; RNA, Messenger/analysis/genetics ; Sequence Analysis, RNA ; Species Specificity
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2011-09-09
    Description: Mutations in the tumour suppressor gene BRCA1 lead to breast and/or ovarian cancer. Here we show that loss of Brca1 in mice results in transcriptional de-repression of the tandemly repeated satellite DNA. Brca1 deficiency is accompanied by a reduction of condensed DNA regions in the genome and loss of ubiquitylation of histone H2A at satellite repeats. BRCA1 binds to satellite DNA regions and ubiquitylates H2A in vivo. Ectopic expression of H2A fused to ubiquitin reverses the effects of BRCA1 loss, indicating that BRCA1 maintains heterochromatin structure via ubiquitylation of histone H2A. Satellite DNA de-repression was also observed in mouse and human BRCA1-deficient breast cancers. Ectopic expression of satellite DNA can phenocopy BRCA1 loss in centrosome amplification, cell-cycle checkpoint defects, DNA damage and genomic instability. We propose that the role of BRCA1 in maintaining global heterochromatin integrity accounts for many of its tumour suppressor functions.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3240576/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3240576/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhu, Quan -- Pao, Gerald M -- Huynh, Alexis M -- Suh, Hoonkyo -- Tonnu, Nina -- Nederlof, Petra M -- Gage, Fred H -- Verma, Inder M -- NS50217/NS/NINDS NIH HHS/ -- NS52842/NS/NINDS NIH HHS/ -- R01 NS050217/NS/NINDS NIH HHS/ -- R01 NS050217-05/NS/NINDS NIH HHS/ -- R01 NS052842/NS/NINDS NIH HHS/ -- R01 NS052842-04/NS/NINDS NIH HHS/ -- England -- Nature. 2011 Sep 7;477(7363):179-84. doi: 10.1038/nature10371.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21901007" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; BRCA1 Protein/deficiency/genetics/*metabolism ; Breast/cytology ; Breast Neoplasms/*genetics/pathology ; Cell Line, Tumor ; Cells, Cultured ; DNA, Satellite/genetics ; Epithelial Cells/metabolism ; Female ; Gene Expression Regulation, Neoplastic ; *Gene Silencing ; Genes, BRCA1/*physiology ; Genomic Instability/genetics ; HeLa Cells ; Heterochromatin/*genetics/*metabolism ; Histones/metabolism ; Humans ; Mice ; Ovarian Neoplasms/genetics ; RNA, Messenger/genetics ; Transcription, Genetic/genetics ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitinated Proteins/metabolism ; Ubiquitination
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
    Publication Date: 2011-04-15
    Description: Schizophrenia (SCZD) is a debilitating neurological disorder with a world-wide prevalence of 1%; there is a strong genetic component, with an estimated heritability of 80-85%. Although post-mortem studies have revealed reduced brain volume, cell size, spine density and abnormal neural distribution in the prefrontal cortex and hippocampus of SCZD brain tissue and neuropharmacological studies have implicated dopaminergic, glutamatergic and GABAergic activity in SCZD, the cell types affected in SCZD and the molecular mechanisms underlying the disease state remain unclear. To elucidate the cellular and molecular defects of SCZD, we directly reprogrammed fibroblasts from SCZD patients into human induced pluripotent stem cells (hiPSCs) and subsequently differentiated these disorder-specific hiPSCs into neurons (Supplementary Fig. 1). SCZD hiPSC neurons showed diminished neuronal connectivity in conjunction with decreased neurite number, PSD95-protein levels and glutamate receptor expression. Gene expression profiles of SCZD hiPSC neurons identified altered expression of many components of the cyclic AMP and WNT signalling pathways. Key cellular and molecular elements of the SCZD phenotype were ameliorated following treatment of SCZD hiPSC neurons with the antipsychotic loxapine. To date, hiPSC neuronal pathology has only been demonstrated in diseases characterized by both the loss of function of a single gene product and rapid disease progression in early childhood. We now report hiPSC neuronal phenotypes and gene expression changes associated with SCZD, a complex genetic psychiatric disorder.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3392969/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3392969/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Brennand, Kristen J -- Simone, Anthony -- Jou, Jessica -- Gelboin-Burkhart, Chelsea -- Tran, Ngoc -- Sangar, Sarah -- Li, Yan -- Mu, Yangling -- Chen, Gong -- Yu, Diana -- McCarthy, Shane -- Sebat, Jonathan -- Gage, Fred H -- P01 NS028121/NS/NINDS NIH HHS/ -- P30 NS072031/NS/NINDS NIH HHS/ -- R01 MH083911/MH/NIMH NIH HHS/ -- England -- Nature. 2011 May 12;473(7346):221-5. doi: 10.1038/nature09915. Epub 2011 Apr 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Salk Institute for Biological Studies, Laboratory of Genetics, 10010 North Torrey Pines Road, La Jolla California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21490598" target="_blank"〉PubMed〈/a〉
    Keywords: Adolescent ; Adult ; Antipsychotic Agents/pharmacology ; Cell Differentiation ; Cells, Cultured ; Cellular Reprogramming/genetics ; Child ; Female ; Fibroblasts/cytology ; Gene Expression Profiling ; *Gene Expression Regulation/drug effects ; Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; Loxapine/pharmacology ; Male ; Membrane Proteins/metabolism ; Models, Biological ; Neurites ; Neurons/*cytology/drug effects/*metabolism ; Phenotype ; Pluripotent Stem Cells/*cytology/*metabolism/pathology ; Receptors, Glutamate/metabolism ; Schizophrenia/*pathology ; Young Adult
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
    Publication Date: 2012-01-27
    Description: Our understanding of Alzheimer's disease pathogenesis is currently limited by difficulties in obtaining live neurons from patients and the inability to model the sporadic form of the disease. It may be possible to overcome these challenges by reprogramming primary cells from patients into induced pluripotent stem cells (iPSCs). Here we reprogrammed primary fibroblasts from two patients with familial Alzheimer's disease, both caused by a duplication of the amyloid-beta precursor protein gene (APP; termed APP(Dp)), two with sporadic Alzheimer's disease (termed sAD1, sAD2) and two non-demented control individuals into iPSC lines. Neurons from differentiated cultures were purified with fluorescence-activated cell sorting and characterized. Purified cultures contained more than 90% neurons, clustered with fetal brain messenger RNA samples by microarray criteria, and could form functional synaptic contacts. Virtually all cells exhibited normal electrophysiological activity. Relative to controls, iPSC-derived, purified neurons from the two APP(Dp) patients and patient sAD2 exhibited significantly higher levels of the pathological markers amyloid-beta(1-40), phospho-tau(Thr 231) and active glycogen synthase kinase-3beta (aGSK-3beta). Neurons from APP(Dp) and sAD2 patients also accumulated large RAB5-positive early endosomes compared to controls. Treatment of purified neurons with beta-secretase inhibitors, but not gamma-secretase inhibitors, caused significant reductions in phospho-Tau(Thr 231) and aGSK-3beta levels. These results suggest a direct relationship between APP proteolytic processing, but not amyloid-beta, in GSK-3beta activation and tau phosphorylation in human neurons. Additionally, we observed that neurons with the genome of one sAD patient exhibited the phenotypes seen in familial Alzheimer's disease samples. More generally, we demonstrate that iPSC technology can be used to observe phenotypes relevant to Alzheimer's disease, even though it can take decades for overt disease to manifest in patients.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3338985/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3338985/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Israel, Mason A -- Yuan, Shauna H -- Bardy, Cedric -- Reyna, Sol M -- Mu, Yangling -- Herrera, Cheryl -- Hefferan, Michael P -- Van Gorp, Sebastiaan -- Nazor, Kristopher L -- Boscolo, Francesca S -- Carson, Christian T -- Laurent, Louise C -- Marsala, Martin -- Gage, Fred H -- Remes, Anne M -- Koo, Edward H -- Goldstein, Lawrence S B -- K12 HD001259/HD/NICHD NIH HHS/ -- P30 NS047101/NS/NINDS NIH HHS/ -- P50 AG005131/AG/NIA NIH HHS/ -- RC1 NS068705/NS/NINDS NIH HHS/ -- RC1 NS068705-01/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Jan 25;482(7384):216-20. doi: 10.1038/nature10821.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22278060" target="_blank"〉PubMed〈/a〉
    Keywords: Aged, 80 and over ; Alzheimer Disease/*metabolism/*pathology ; Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism ; Amyloid beta-Peptides/metabolism/secretion ; Amyloid beta-Protein Precursor/genetics/metabolism/secretion ; Astrocytes/cytology ; Biomarkers/metabolism ; Cells, Cultured ; Cellular Reprogramming ; Coculture Techniques ; Endosomes/metabolism ; Enzyme Activation ; Female ; Fibroblasts/cytology/metabolism ; Glycogen Synthase Kinase 3/metabolism ; Humans ; Induced Pluripotent Stem Cells/*metabolism/*pathology ; Male ; Middle Aged ; Models, Biological ; Neurons/drug effects/*metabolism/pathology ; Peptide Fragments/metabolism/secretion ; Phosphoproteins/metabolism ; Phosphorylation/drug effects ; Protease Inhibitors/pharmacology ; Proteolysis ; Synapsins/metabolism ; tau Proteins/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 9
    Publication Date: 2013-10-11
    Description: Progressive phases of multiple sclerosis are associated with inhibited differentiation of the progenitor cell population that generates the mature oligodendrocytes required for remyelination and disease remission. To identify selective inducers of oligodendrocyte differentiation, we performed an image-based screen for myelin basic protein (MBP) expression using primary rat optic-nerve-derived progenitor cells. Here we show that among the most effective compounds identifed was benztropine, which significantly decreases clinical severity in the experimental autoimmune encephalomyelitis (EAE) model of relapsing-remitting multiple sclerosis when administered alone or in combination with approved immunosuppressive treatments for multiple sclerosis. Evidence from a cuprizone-induced model of demyelination, in vitro and in vivo T-cell assays and EAE adoptive transfer experiments indicated that the observed efficacy of this drug results directly from an enhancement of remyelination rather than immune suppression. Pharmacological studies indicate that benztropine functions by a mechanism that involves direct antagonism of M1 and/or M3 muscarinic receptors. These studies should facilitate the development of effective new therapies for the treatment of multiple sclerosis that complement established immunosuppressive approaches.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4431622/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4431622/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Deshmukh, Vishal A -- Tardif, Virginie -- Lyssiotis, Costas A -- Green, Chelsea C -- Kerman, Bilal -- Kim, Hyung Joon -- Padmanabhan, Krishnan -- Swoboda, Jonathan G -- Ahmad, Insha -- Kondo, Toru -- Gage, Fred H -- Theofilopoulos, Argyrios N -- Lawson, Brian R -- Schultz, Peter G -- Lairson, Luke L -- K99 MH101634/MH/NIMH NIH HHS/ -- R01 AR053228/AR/NIAMS NIH HHS/ -- R21 AR065384/AR/NIAMS NIH HHS/ -- R37 AR039555/AR/NIAMS NIH HHS/ -- England -- Nature. 2013 Oct 17;502(7471):327-32. doi: 10.1038/nature12647. Epub 2013 Oct 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, The Scripps Research Institute, 10550, North Torrey Pines Road, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24107995" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antiparkinson Agents/pharmacology/therapeutic use ; Benztropine/pharmacology/*therapeutic use ; Cell Differentiation/drug effects ; Coculture Techniques ; Cuprizone/pharmacology/therapeutic use ; Encephalomyelitis, Autoimmune, Experimental/chemically induced/*drug ; therapy/pathology ; Female ; Fingolimod Hydrochloride ; Immune System/drug effects/immunology ; Mice ; Mice, Inbred C57BL ; *Models, Biological ; Multiple Sclerosis/*drug therapy/pathology ; Myelin Proteolipid Protein/pharmacology ; Myelin Sheath/*drug effects/metabolism/pathology ; Oligodendroglia/cytology/*drug effects/metabolism/pathology ; Optic Nerve/cytology ; Propylene Glycols/pharmacology/therapeutic use ; Rats ; Receptor, Muscarinic M1/antagonists & inhibitors/metabolism ; Receptor, Muscarinic M3/antagonists & inhibitors/metabolism ; Recurrence ; Regeneration/*drug effects ; Sphingosine/analogs & derivatives/pharmacology/therapeutic use ; Stem Cells/cytology/drug effects
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
    Publication Date: 2015-11-26
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mertens, Jerome -- Wang, Qiu-Wen -- Kim, Yongsung -- Yu, Diana X -- Pham, Son -- Yang, Bo -- Zheng, Yi -- Diffenderfer, Kenneth E -- Zhang, Jian -- Soltani, Sheila -- Eames, Tameji -- Schafer, Simon T -- Boyer, Leah -- Marchetto, Maria C -- Nurnberger, John I -- Calabrese, Joseph R -- Oedegaard, Ketil J -- McCarthy, Michael J -- Zandi, Peter P -- Alda, Martin -- Nievergelt, Caroline M -- Pharmacogenomics of Bipolar Disorder Study -- Mi, Shuangli -- Brennand, Kristen J -- Kelsoe, John R -- Gage, Fred H -- Yao, Jun -- England -- Nature. 2016 Feb 11;530(7589):242. doi: 10.1038/nature16182. Epub 2015 Nov 25.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26605530" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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