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  • 1
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    The C9orf72 repeat expansion disrupts nucleocytoplasmic transport (2015)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2015-08-27
    Description: The hexanucleotide repeat expansion (HRE) GGGGCC (G4C2) in C9orf72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent studies support an HRE RNA gain-of-function mechanism of neurotoxicity, and we previously identified protein interactors for the G4C2 RNA including RanGAP1. A candidate-based genetic screen in Drosophila expressing 30 G4C2 repeats identified RanGAP (Drosophila orthologue of human RanGAP1), a key regulator of nucleocytoplasmic transport, as a potent suppressor of neurodegeneration. Enhancing nuclear import or suppressing nuclear export of proteins also suppresses neurodegeneration. RanGAP physically interacts with HRE RNA and is mislocalized in HRE-expressing flies, neurons from C9orf72 ALS patient-derived induced pluripotent stem cells (iPSC-derived neurons), and in C9orf72 ALS patient brain tissue. Nuclear import is impaired as a result of HRE expression in the fly model and in C9orf72 iPSC-derived neurons, and these deficits are rescued by small molecules and antisense oligonucleotides targeting the HRE G-quadruplexes. Nucleocytoplasmic transport defects may be a fundamental pathway for ALS and FTD that is amenable to pharmacotherapeutic intervention.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Ke -- Donnelly, Christopher J -- Haeusler, Aaron R -- Grima, Jonathan C -- Machamer, James B -- Steinwald, Peter -- Daley, Elizabeth L -- Miller, Sean J -- Cunningham, Kathleen M -- Vidensky, Svetlana -- Gupta, Saksham -- Thomas, Michael A -- Hong, Ingie -- Chiu, Shu-Ling -- Huganir, Richard L -- Ostrow, Lyle W -- Matunis, Michael J -- Wang, Jiou -- Sattler, Rita -- Lloyd, Thomas E -- Rothstein, Jeffrey D -- CA009110/CA/NCI NIH HHS/ -- K99 NS091486/NS/NINDS NIH HHS/ -- NS089616/NS/NINDS NIH HHS/ -- NS091046/NS/NINDS NIH HHS/ -- P01 AG012992/AG/NIA NIH HHS/ -- P40OD018537/OD/NIH HHS/ -- R01 NS074324/NS/NINDS NIH HHS/ -- R01 NS082563/NS/NINDS NIH HHS/ -- R01 NS085207/NS/NINDS NIH HHS/ -- R01 NS089616/NS/NINDS NIH HHS/ -- R01-GM084947/GM/NIGMS NIH HHS/ -- R01NS085207/NS/NINDS NIH HHS/ -- RC2 NS069395/NS/NINDS NIH HHS/ -- T32 CA009110/CA/NCI NIH HHS/ -- U24 NS078736/NS/NINDS NIH HHS/ -- U54 NS091046/NS/NINDS NIH HHS/ -- England -- Nature. 2015 Sep 3;525(7567):56-61. doi: 10.1038/nature14973. Epub 2015 Aug 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurology, School of Medicine, Johns Hopkins University, Maryland 21205, USA. ; Brain Science Institute, School of Medicine, Johns Hopkins University, Maryland 21205, USA. ; Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Maryland 21205, USA. ; Department of Neuroscience, School of Medicine, Johns Hopkins University, Maryland 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26308891" target="_blank"〉PubMed〈/a〉
    Keywords: Active Transport, Cell Nucleus/*genetics ; Amyotrophic Lateral Sclerosis/genetics/pathology ; Animals ; Brain/metabolism/pathology ; Cell Nucleus/*metabolism ; DNA Repeat Expansion/*genetics ; Drosophila Proteins/metabolism ; Drosophila melanogaster/cytology/metabolism ; Female ; Frontotemporal Dementia/genetics/pathology ; G-Quadruplexes ; GTPase-Activating Proteins/metabolism ; Humans ; Induced Pluripotent Stem Cells/cytology/metabolism ; Neurons/metabolism/pathology ; Nuclear Pore/chemistry/metabolism ; Nuclear Proteins/metabolism ; Oligonucleotides, Antisense/genetics ; Open Reading Frames/*genetics ; Proteins/*genetics ; RNA/genetics/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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    Paraquat neurotoxicity is mediated by the dopamine transporter and organic cation transporter-3 (2011)
    National Academy of Sciences
    Details
    Publication Date: 2011-12-05
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 3
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    Neural dysfunction in HD linked to IPMK [Neuroscience] (2015)
    National Academy of Sciences
    Details
    Publication Date: 2015-08-05
    Description: Huntington’s disease (HD) is a progressive neurodegenerative disease caused by a glutamine repeat expansion in mutant huntingtin (mHtt). Despite the known genetic cause of HD, the pathophysiology of this disease remains to be elucidated. Inositol polyphosphate multikinase (IPMK) is an enzyme that displays soluble inositol phosphate kinase activity, lipid kinase...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 4
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    Liquid-filled canyons on Titan (2016)
    Wiley
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    Publication Date: 2016-08-10
    Description: In May 2013 the Cassini RADAR altimeter observed channels in Vid Flumina, a drainage network connected to Titan's second largest hydrocarbon sea, Ligeia Mare. Analysis of these altimeter echoes shows that the channels are located in deep (up to ~570 m), steep-sided, canyons and have strong specular surface reflections that indicate they are currently liquid filled. Elevations of the liquid in these channels are at the same level as Ligeia Mare to within a vertical precision of about 0.7 m, consistent with the interpretation of drowned river valleys. Specular reflections are also observed in lower order tributaries elevated above the level of Ligeia Mare, consistent with drainage feeding into the main channel system.
    Print ISSN: 0094-8276
    Electronic ISSN: 1944-8007
    Topics: Geosciences , Physics
    Published by Wiley on behalf of American Geophysical Union (AGU).
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  • 5
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    Paraquat neurotoxicity is mediated by the dopamine transporter and organic cation transporter-3 [Neuroscience] (2011)
    National Academy of Sciences
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    Publication Date: 2011-12-21
    Description: The herbicide paraquat (PQ) has increasingly been reported in epidemiological studies to enhance the risk of developing Parkinson's disease (PD). Furthermore, case-control studies report that individuals with genetic variants in the dopamine transporter (DAT, SLC6A) have a higher PD risk when exposed to PQ. However, it remains a topic of debate whether PQ can enter dopamine (DA) neurons through DAT. We report here a mechanism by which PQ is transported by DAT: In its native divalent cation state, PQ2+ is not a substrate for DAT; however, when converted to the monovalent cation PQ+ by either a reducing agent or NADPH oxidase on microglia, it becomes a substrate for DAT and is accumulated in DA neurons, where it induces oxidative stress and cytotoxicity. Impaired DAT function in cultured cells and mutant mice significantly attenuated neurotoxicity induced by PQ+. In addition to DAT, PQ+ is also a substrate for the organic cation transporter 3 (Oct3, Slc22a3), which is abundantly expressed in non-DA cells in the nigrostriatal regions. In mice with Oct3 deficiency, enhanced striatal damage was detected after PQ treatment. This increased sensitivity likely results from reduced buffering capacity by non-DA cells, leading to more PQ+ being available for uptake by DA neurons. This study provides a mechanism by which DAT and Oct3 modulate nigrostriatal damage induced by PQ2+/PQ+ redox cycling.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 6
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    Total Electron Content in the martian atmosphere: a critical assessment of the Mars Express MARSIS datasets (2015)
    Wiley
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    Publication Date: 2015-02-06
    Description: The total electron content (TEC) is one of the most useful parameters to evaluate the behavior of the martian ionosphere because it contains information on the total amount of free electrons, the main component of the martian ionospheric plasma. The Mars Express MARSIS radar is able to derive TEC from both of its operations modes: (1) the active ionospheric sounding (AIS) mode, and (2) the subsurface mode. TEC estimates from the subsurface sounding mode can be computed from the same raw data independently using different algorithms, which should yield similar results. Significant differences on the dayside, however, have been found from two of the algorithms. Moreover, both algorithms seem also to disagree with the TEC results from the AIS mode. This paper gives a critical, quantitative and independent assessment of these discrepancies, and indicates the possible uncertainty of these databases. In addition, a comparison between the results given by the empirical model of the martian ionosphere developed by Sánchez-Cano et al. (2013) and the different datasets has been performed. The main result is that for solar zenith angles higher than 75 degrees, where the maximum plasma frequency is typically small compared with the radar frequencies, the two subsurface algorithms can be confidently used. For solar zenith angles less than 75 degrees, where the maximum plasma frequency is very close to the radar frequencies, both algorithms suffer limitations. Nevertheless, despite the solar zenith angle restrictions, the dayside TEC of one of the two algorithms is consistent with the modelled TEC.
    Print ISSN: 0148-0227
    Topics: Geosciences , Physics
    Published by Wiley on behalf of American Geophysical Union (AGU).
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