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  • 1
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    Neurodegeneration. C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-05-16
    Description: The major genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis is a G4C2 repeat expansion in C9ORF72. Efforts to combat neurodegeneration associated with "c9FTD/ALS" are hindered by a lack of animal models recapitulating disease features. We developed a mouse model to mimic both neuropathological and clinical c9FTD/ALS phenotypes. We expressed (G4C2)66 throughout the murine central nervous system by means of somatic brain transgenesis mediated by adeno-associated virus. Brains of 6-month-old mice contained nuclear RNA foci, inclusions of poly(Gly-Pro), poly(Gly-Ala), and poly(Gly-Arg) dipeptide repeat proteins, as well as TDP-43 pathology. These mouse brains also exhibited cortical neuron and cerebellar Purkinje cell loss, astrogliosis, and decreased weight. (G4C2)66 mice also developed behavioral abnormalities similar to clinical symptoms of c9FTD/ALS patients, including hyperactivity, anxiety, antisocial behavior, and motor deficits.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4692360/" 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/PMC4692360/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chew, Jeannie -- Gendron, Tania F -- Prudencio, Mercedes -- Sasaguri, Hiroki -- Zhang, Yong-Jie -- Castanedes-Casey, Monica -- Lee, Chris W -- Jansen-West, Karen -- Kurti, Aishe -- Murray, Melissa E -- Bieniek, Kevin F -- Bauer, Peter O -- Whitelaw, Ena C -- Rousseau, Linda -- Stankowski, Jeannette N -- Stetler, Caroline -- Daughrity, Lillian M -- Perkerson, Emilie A -- Desaro, Pamela -- Johnston, Amelia -- Overstreet, Karen -- Edbauer, Dieter -- Rademakers, Rosa -- Boylan, Kevin B -- Dickson, Dennis W -- Fryer, John D -- Petrucelli, Leonard -- P01 NS084974/NS/NINDS NIH HHS/ -- P01NS084974/NS/NINDS NIH HHS/ -- P50 AG016574/AG/NIA NIH HHS/ -- P50AG016574/AG/NIA NIH HHS/ -- R01 NS077402/NS/NINDS NIH HHS/ -- R01ES20395/ES/NIEHS NIH HHS/ -- R01NS063964/NS/NINDS NIH HHS/ -- R01NS077402/NS/NINDS NIH HHS/ -- R01NS088689/NS/NINDS NIH HHS/ -- R21 NS084528/NS/NINDS NIH HHS/ -- R21NS079807/NS/NINDS NIH HHS/ -- R21NS084528/NS/NINDS NIH HHS/ -- R21NS089979/NS/NINDS NIH HHS/ -- New York, N.Y. -- Science. 2015 Jun 5;348(6239):1151-4. doi: 10.1126/science.aaa9344. Epub 2015 May 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. ; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. ; Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. ; German Center for Neurodegenerative Diseases (DZNE) Munich, Feodor-Lynen-Strasse 17, 81337 Munich, Germany. Institute for Metabolic Biochemistry, Ludwig-Maximilians University Munich, Feodor-Lynen-Strasse 17, 81337 Munich, Germany. Munich Cluster of Systems Neurology (SyNergy), Munich, Germany. ; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. petrucelli.leonard@mayo.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25977373" target="_blank"〉PubMed〈/a〉
    Keywords: Amyotrophic Lateral Sclerosis/*genetics/pathology ; Animals ; Antisocial Personality Disorder/genetics/pathology ; Cerebral Cortex/metabolism/pathology ; DNA-Binding Proteins/*genetics ; Dependovirus ; Dipeptides/metabolism ; *Disease Models, Animal ; Frontotemporal Dementia/*genetics/pathology ; Gene Transfer Techniques ; HEK293 Cells ; Humans ; *Mice ; Proteins/*genetics ; Purkinje Cells/metabolism/pathology ; RNA, Nuclear/metabolism
    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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  • 2
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    The dual functions of the extreme N-terminus of TDP-43 in regulating its biological activity and inclusion formation (2013)
    Oxford University Press
    Details
    Publication Date: 2013-07-03
    Description: TAR DNA-binding protein-43 (TDP-43) is the principal component of ubiquitinated inclusions in amyotrophic lateral sclerosis (ALS) and the most common pathological subtype of frontotemporal dementia—frontotemporal lobar degeneration with TDP-43-positive inclusions (FTLD-TDP). To date, the C-terminus of TDP-43, which is aggregation-prone and contains almost all ALS-associated mutations, has garnered much attention while the functions of the N-terminus of TDP-43 remain largely unknown. To bridge this gap in our knowledge, we utilized novel cell culture and computer-assisted models to evaluate which region(s) of TDP-43 regulate its folding, self-interaction, biological activity and aggregation. We determined that the extreme N-terminus of TDP-43, specifically the first 10 residues, regulates folding of TDP-43 monomers necessary for proper homodimerization and TDP-43-regulated splicing. Despite such beneficial functions, we discovered an interesting dichotomy: full-length TDP-43 aggregation, which is believed to be a pathogenic process, also requires the extreme N-terminus of TDP-43. As such, we provide new insight into the structural basis for TDP-43 function and aggregation, and we suggest that stabilization of TDP-43 homodimers, the physiologically active form of TDP-43, may be a promising therapeutic strategy for ALS and FTLD-TDP.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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