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  • 1
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    RAS-MAPK-MSK1 pathway modulates ataxin 1 protein levels and toxicity in SCA1 (2013)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2013-05-31
    Description: Many neurodegenerative disorders, such as Alzheimer's, Parkinson's and polyglutamine diseases, share a common pathogenic mechanism: the abnormal accumulation of disease-causing proteins, due to either the mutant protein's resistance to degradation or overexpression of the wild-type protein. We have developed a strategy to identify therapeutic entry points for such neurodegenerative disorders by screening for genetic networks that influence the levels of disease-driving proteins. We applied this approach, which integrates parallel cell-based and Drosophila genetic screens, to spinocerebellar ataxia type 1 (SCA1), a disease caused by expansion of a polyglutamine tract in ataxin 1 (ATXN1). Our approach revealed that downregulation of several components of the RAS-MAPK-MSK1 pathway decreases ATXN1 levels and suppresses neurodegeneration in Drosophila and mice. Importantly, pharmacological inhibitors of components of this pathway also decrease ATXN1 levels, suggesting that these components represent new therapeutic targets in mitigating SCA1. Collectively, these data reveal new therapeutic entry points for SCA1 and provide a proof-of-principle for tackling other classes of intractable neurodegenerative diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4020154/" 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/PMC4020154/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Park, Jeehye -- Al-Ramahi, Ismael -- Tan, Qiumin -- Mollema, Nissa -- Diaz-Garcia, Javier R -- Gallego-Flores, Tatiana -- Lu, Hsiang-Chih -- Lagalwar, Sarita -- Duvick, Lisa -- Kang, Hyojin -- Lee, Yoontae -- Jafar-Nejad, Paymaan -- Sayegh, Layal S -- Richman, Ronald -- Liu, Xiuyun -- Gao, Yan -- Shaw, Chad A -- Arthur, J Simon C -- Orr, Harry T -- Westbrook, Thomas F -- Botas, Juan -- Zoghbi, Huda Y -- HD024064/HD/NICHD NIH HHS/ -- MC_U127081014/Medical Research Council/United Kingdom -- NS42179/NS/NINDS NIH HHS/ -- P30 HD024064/HD/NICHD NIH HHS/ -- R01 NS027699/NS/NINDS NIH HHS/ -- R01 NS042179/NS/NINDS NIH HHS/ -- T32 GM007526/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Jun 20;498(7454):325-31. doi: 10.1038/nature12204. Epub 2013 May 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23719381" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Animals, Genetically Modified ; Ataxin-1 ; Ataxins ; Cell Line, Tumor ; Disease Models, Animal ; Down-Regulation/drug effects ; Drosophila melanogaster/genetics/*metabolism ; Female ; Humans ; MAP Kinase Signaling System/drug effects ; Male ; Mice ; Mitogen-Activated Protein Kinases/*metabolism ; Molecular Sequence Data ; Molecular Targeted Therapy ; Nerve Tissue Proteins/chemistry/genetics/*metabolism/*toxicity ; Nuclear Proteins/chemistry/genetics/*metabolism/*toxicity ; Phosphorylation ; Protein Stability/drug effects ; Ribosomal Protein S6 Kinases, 90-kDa/deficiency/genetics/*metabolism ; Spinocerebellar Ataxias/*metabolism/*pathology ; Transgenes ; ras Proteins/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Genome sequencing reveals insights into physiology and longevity of the naked mole rat (2011)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2011-10-14
    Description: The naked mole rat (Heterocephalus glaber) is a strictly subterranean, extraordinarily long-lived eusocial mammal. Although it is the size of a mouse, its maximum lifespan exceeds 30 years, making this animal the longest-living rodent. Naked mole rats show negligible senescence, no age-related increase in mortality, and high fecundity until death. In addition to delayed ageing, they are resistant to both spontaneous cancer and experimentally induced tumorigenesis. Naked mole rats pose a challenge to the theories that link ageing, cancer and redox homeostasis. Although characterized by significant oxidative stress, the naked mole rat proteome does not show age-related susceptibility to oxidative damage or increased ubiquitination. Naked mole rats naturally reside in large colonies with a single breeding female, the 'queen', who suppresses the sexual maturity of her subordinates. They also live in full darkness, at low oxygen and high carbon dioxide concentrations, and are unable to sustain thermogenesis nor feel certain types of pain. Here we report the sequencing and analysis of the naked mole rat genome, which reveals unique genome features and molecular adaptations consistent with cancer resistance, poikilothermy, hairlessness and insensitivity to low oxygen, and altered visual function, circadian rythms and taste sensing. This information provides insights into the naked mole rat's exceptional longevity and ability to live in hostile conditions, in the dark and at low oxygen. The extreme traits of the naked mole rat, together with the reported genome and transcriptome information, offer opportunities for understanding ageing and advancing other areas of biological and biomedical research.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319411/" 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/PMC3319411/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Eun Bae -- Fang, Xiaodong -- Fushan, Alexey A -- Huang, Zhiyong -- Lobanov, Alexei V -- Han, Lijuan -- Marino, Stefano M -- Sun, Xiaoqing -- Turanov, Anton A -- Yang, Pengcheng -- Yim, Sun Hee -- Zhao, Xiang -- Kasaikina, Marina V -- Stoletzki, Nina -- Peng, Chunfang -- Polak, Paz -- Xiong, Zhiqiang -- Kiezun, Adam -- Zhu, Yabing -- Chen, Yuanxin -- Kryukov, Gregory V -- Zhang, Qiang -- Peshkin, Leonid -- Yang, Lan -- Bronson, Roderick T -- Buffenstein, Rochelle -- Wang, Bo -- Han, Changlei -- Li, Qiye -- Chen, Li -- Zhao, Wei -- Sunyaev, Shamil R -- Park, Thomas J -- Zhang, Guojie -- Wang, Jun -- Gladyshev, Vadim N -- AG021518/AG/NIA NIH HHS/ -- AG038004/AG/NIA NIH HHS/ -- CA080946/CA/NCI NIH HHS/ -- R01 AG021518/AG/NIA NIH HHS/ -- R01 AG021518-10/AG/NIA NIH HHS/ -- R01 AG038004/AG/NIA NIH HHS/ -- R01 AG038004-02/AG/NIA NIH HHS/ -- R01 CA080946/CA/NCI NIH HHS/ -- R01 CA080946-11/CA/NCI NIH HHS/ -- England -- Nature. 2011 Oct 12;479(7372):223-7. doi: 10.1038/nature10533.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Bioinspired Science, Ewha Womans University, Seoul, 120-750, Korea.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21993625" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptation, Physiological/*genetics ; Aging/genetics ; Amino Acid Sequence ; Animals ; Body Temperature Regulation/genetics ; Carbon Dioxide/analysis/metabolism ; Circadian Rhythm/genetics ; Darkness ; Genes/genetics ; Genome/*genetics ; Genomic Instability/genetics ; Genomics ; Humans ; Ion Channels/genetics ; Longevity/*genetics/physiology ; Male ; Mitochondrial Proteins/genetics ; Mole Rats/*genetics/*physiology ; Molecular Sequence Data ; Mutagenesis/genetics ; Oxygen/analysis/metabolism ; Taste/genetics ; Transcriptome/genetics ; Visual Perception/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies (2010)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2010-03-06
    Description: Sestrins are conserved proteins that accumulate in cells exposed to stress, potentiate adenosine monophosphate-activated protein kinase (AMPK), and inhibit activation of target of rapamycin (TOR). We show that the abundance of Drosophila sestrin (dSesn) is increased upon chronic TOR activation through accumulation of reactive oxygen species that cause activation of c-Jun amino-terminal kinase and transcription factor Forkhead box O (FoxO). Loss of dSesn resulted in age-associated pathologies including triglyceride accumulation, mitochondrial dysfunction, muscle degeneration, and cardiac malfunction, which were prevented by pharmacological activation of AMPK or inhibition of TOR. Hence, dSesn appears to be a negative feedback regulator of TOR that integrates metabolic and stress inputs and prevents pathologies caused by chronic TOR activation that may result from diminished autophagic clearance of damaged mitochondria, protein aggregates, or lipids.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2866632/" 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/PMC2866632/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Jun Hee -- Budanov, Andrei V -- Park, Eek Joong -- Birse, Ryan -- Kim, Teddy E -- Perkins, Guy A -- Ocorr, Karen -- Ellisman, Mark H -- Bodmer, Rolf -- Bier, Ethan -- Karin, Michael -- AI070654/AI/NIAID NIH HHS/ -- CA118165/CA/NCI NIH HHS/ -- DK082080/DK/NIDDK NIH HHS/ -- ES006376/ES/NIEHS NIH HHS/ -- NS29870/NS/NINDS NIH HHS/ -- P30 CA023100/CA/NCI NIH HHS/ -- P30-CA23100/CA/NCI NIH HHS/ -- P41-RR004050/RR/NCRR NIH HHS/ -- P42 ES010337/ES/NIEHS NIH HHS/ -- P42 ES010337-10S20010/ES/NIEHS NIH HHS/ -- P42-ES010337/ES/NIEHS NIH HHS/ -- R01 CA118165/CA/NCI NIH HHS/ -- R01 CA118165-04/CA/NCI NIH HHS/ -- R01 ES006376/ES/NIEHS NIH HHS/ -- R01 ES006376-17/ES/NIEHS NIH HHS/ -- New York, N.Y. -- Science. 2010 Mar 5;327(5970):1223-8. doi: 10.1126/science.1182228.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093-0723, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20203043" target="_blank"〉PubMed〈/a〉
    Keywords: AMP-Activated Protein Kinases/metabolism ; *Aging ; Amino Acid Sequence ; Animals ; Autophagy ; Cell Size ; Drosophila Proteins/antagonists & ; inhibitors/chemistry/genetics/metabolism/*physiology ; Drosophila melanogaster/cytology/growth & development/metabolism/*physiology ; Fat Body/metabolism ; Feedback, Physiological ; Forkhead Transcription Factors/metabolism ; Gene Expression Regulation ; Heart/physiology ; Heat-Shock Proteins/chemistry/genetics/*physiology ; JNK Mitogen-Activated Protein Kinases/metabolism ; Mitochondria, Muscle/physiology/ultrastructure ; Models, Animal ; Molecular Sequence Data ; Muscles/physiology ; Oxidative Stress ; Protein Kinases/*metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; TOR Serine-Threonine Kinases ; Transcription, Genetic ; Triglycerides/metabolism ; Wings, Animal/cytology/growth & development/metabolism
    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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  • 4
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    Atomic view of a toxic amyloid small oligomer (2012)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2012-03-10
    Description: Amyloid diseases, including Alzheimer's, Parkinson's, and the prion conditions, are each associated with a particular protein in fibrillar form. These amyloid fibrils were long suspected to be the disease agents, but evidence suggests that smaller, often transient and polymorphic oligomers are the toxic entities. Here, we identify a segment of the amyloid-forming protein alphaB crystallin, which forms an oligomeric complex exhibiting properties of other amyloid oligomers: beta-sheet-rich structure, cytotoxicity, and recognition by an oligomer-specific antibody. The x-ray-derived atomic structure of the oligomer reveals a cylindrical barrel, formed from six antiparallel protein strands, that we term a cylindrin. The cylindrin structure is compatible with a sequence segment from the beta-amyloid protein of Alzheimer's disease. Cylindrins offer models for the hitherto elusive structures of amyloid oligomers.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3959867/" 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/PMC3959867/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Laganowsky, Arthur -- Liu, Cong -- Sawaya, Michael R -- Whitelegge, Julian P -- Park, Jiyong -- Zhao, Minglei -- Pensalfini, Anna -- Soriaga, Angela B -- Landau, Meytal -- Teng, Poh K -- Cascio, Duilio -- Glabe, Charles -- Eisenberg, David -- 016570/PHS HHS/ -- 1R01-AG029430/AG/NIA NIH HHS/ -- 5T32GM008496/GM/NIGMS NIH HHS/ -- P50 AG016570/AG/NIA NIH HHS/ -- R01 AG029430/AG/NIA NIH HHS/ -- R01 AG033069/AG/NIA NIH HHS/ -- RR-15301/RR/NCRR NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2012 Mar 9;335(6073):1228-31. doi: 10.1126/science.1213151.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Chemistry, University of California Los Angeles (UCLA), Howard Hughes Medical Institute (HHMI), Los Angeles, CA 90095, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22403391" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Amyloid/*chemistry/immunology ; Amyloid beta-Peptides/chemistry ; Antibodies/immunology ; Crystallography, X-Ray ; Hydrogen Bonding ; Models, Molecular ; Molecular Dynamics Simulation ; Molecular Sequence Data ; Peptide Fragments/*chemistry/immunology ; Protein Conformation ; Protein Structure, Tertiary ; Recombinant Proteins/chemistry ; alpha-Crystallin B Chain/*chemistry/immunology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 5
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    Landscape of somatic retrotransposition in human cancers (2012)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2012-06-30
    Description: Transposable elements (TEs) are abundant in the human genome, and some are capable of generating new insertions through RNA intermediates. In cancer, the disruption of cellular mechanisms that normally suppress TE activity may facilitate mutagenic retrotranspositions. We performed single-nucleotide resolution analysis of TE insertions in 43 high-coverage whole-genome sequencing data sets from five cancer types. We identified 194 high-confidence somatic TE insertions, as well as thousands of polymorphic TE insertions in matched normal genomes. Somatic insertions were present in epithelial tumors but not in blood or brain cancers. Somatic L1 insertions tend to occur in genes that are commonly mutated in cancer, disrupt the expression of the target genes, and are biased toward regions of cancer-specific DNA hypomethylation, highlighting their potential impact in tumorigenesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3656569/" 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/PMC3656569/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Eunjung -- Iskow, Rebecca -- Yang, Lixing -- Gokcumen, Omer -- Haseley, Psalm -- Luquette, Lovelace J 3rd -- Lohr, Jens G -- Harris, Christopher C -- Ding, Li -- Wilson, Richard K -- Wheeler, David A -- Gibbs, Richard A -- Kucherlapati, Raju -- Lee, Charles -- Kharchenko, Peter V -- Park, Peter J -- Cancer Genome Atlas Research Network -- F32 AG039979/AG/NIA NIH HHS/ -- F32AG039979/AG/NIA NIH HHS/ -- K25 AG037596/AG/NIA NIH HHS/ -- K25AG037596/AG/NIA NIH HHS/ -- R01 GM082798/GM/NIGMS NIH HHS/ -- R01GM082798/GM/NIGMS NIH HHS/ -- RC1HG005482/HG/NHGRI NIH HHS/ -- T32 CA009172/CA/NCI NIH HHS/ -- U01 HG005725/HG/NHGRI NIH HHS/ -- U01HG005209/HG/NHGRI NIH HHS/ -- U01HG005725/HG/NHGRI NIH HHS/ -- U24 CA144025/CA/NCI NIH HHS/ -- U24CA144025/CA/NCI NIH HHS/ -- U54 HG003273/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2012 Aug 24;337(6097):967-71. doi: 10.1126/science.1222077. Epub 2012 Jun 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22745252" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Cell Transformation, Neoplastic ; Colorectal Neoplasms/*genetics ; DNA Methylation ; Female ; Gene Expression Regulation, Neoplastic ; Genes, Neoplasm ; Genome, Human ; Glioblastoma/*genetics ; Humans ; Long Interspersed Nucleotide Elements ; Male ; Microsatellite Instability ; Molecular Sequence Annotation ; Molecular Sequence Data ; Multiple Myeloma/*genetics ; Mutagenesis, Insertional ; Mutation ; Ovarian Neoplasms/*genetics ; Prostatic Neoplasms/*genetics ; *Retroelements ; Sequence Analysis, DNA
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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