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foci, repeat, cells, rna, inclusions, antisense, proteins, corf, article, transcripts, ccccgg, cftdals, polygp, translation, google, scholar, ran, pubmed, ggggcc, expanded, sense, cas, cortex, cran, fig, cerebellum, repeats, frontal, cases, expression, antibodies, cell, structure, nuclear, expansion, present, patients, secondary, ccccggexp, antibody, hexanucleotide, tissue, probe, analysis, formation, van, polypr, polypa, neuronal, percentage,

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sulfo-tag™-rabbit secondary antibody chromosome 9p21-linked als-ftd aggregating dipeptide-repeat proteins formalin-fixed paraffin-embedded tissue chromosome 9p-linked ftd amyotrophic lateral sclerosis article download pdf g-quadruplex conformational transition human post-mortem tissue cross-sectional cohort study scale bar 10 μm scale bar 5 μm p62-positive/tdp43-negative inclusions related subjects anti-pr immunoreactive-inclusion burden scale bars 10 μm ipsc-derived human neurons show modest cross-reactivity 10 % tris–glycine sds-page c9ran inclusions correlate express enhanced gfp-tagged characteristic “star-shaped” morphology n-expressing cells shows atg-initiated translation directed diffuse neuronal “pre-inclusions” paraffin-embedded frontal cortex 1 mg/ml yeast trna micron-thick tissue sections post-fish immunofluorescent staining aggregation-prone proteins involved exp-derived rna foci frontotemporal lobar degeneration tye563-labeled lna probe full access disease research center vectashield-dapi mounting medium flanders-belgian cohort cag repeat disorders c9orf72 hexanucleotide repeat c9orf72 expanded repeat expanded c9orf72 repeat test potential cross-reactivity expanded hexanucleotide repeat c9orf72 hexanucleotide expansion pre-mrna targets antisense transcript-derived poly secondary structure prediction frontotemporal dementia genetics privacy choices/manage cookies form imperfect hairpins

Questions {❓}

• Lomen-Hoerth C, Murphy J, Langmore S, Kramer JH, Olney RK, Miller B (2003) Are amyotrophic lateral sclerosis patients cognitively normal?

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         headline:Antisense transcripts of the expanded C9ORF72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation in c9FTD/ALS
         description:Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are devastating neurodegenerative disorders with clinical, genetic, and neuropathological overlap. A hexanucleotide (GGGGCC) repeat expansion in a non-coding region of C9ORF72 is the major genetic cause of both diseases. The mechanisms by which this repeat expansion causes “c9FTD/ALS” are not definitively known, but RNA-mediated toxicity is a likely culprit. RNA transcripts of the expanded GGGGCC repeat form nuclear foci in c9FTD/ALS, and also undergo repeat-associated non-ATG (RAN) translation resulting in the production of three aggregation-prone proteins. The goal of this study was to examine whether antisense transcripts resulting from bidirectional transcription of the expanded repeat behave in a similar manner. We show that ectopic expression of (CCCCGG)66 in cultured cells results in foci formation. Using novel polyclonal antibodies for the detection of possible (CCCCGG)exp RAN proteins [poly(PR), poly(GP) and poly(PA)], we validated that (CCCCGG)66 is also subject to RAN translation in transfected cells. Of importance, foci composed of antisense transcripts are observed in the frontal cortex, spinal cord and cerebellum of c9FTD/ALS cases, and neuronal inclusions of poly(PR), poly(GP) and poly(PA) are present in various brain tissues in c9FTD/ALS, but not in other neurodegenerative diseases, including CAG repeat disorders. Of note, RNA foci and poly(GP) inclusions infrequently co-occur in the same cell, suggesting these events represent two distinct ways in which the C9ORF72 repeat expansion may evoke neurotoxic effects. These findings provide mechanistic insight into the pathogenesis of c9FTD/ALS, and have significant implications for therapeutic strategies.
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         Bidirectional transcription
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         Expanded repeat
         Frontotemporal dementia
         Repeat-associated non-ATG translation
         RNA foci
         Pathology
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               name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
               type:PostalAddress
            type:Organization
      name:Judith H. Dunmore
      affiliation:
            name:Mayo Clinic Florida
            address:
               name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
               type:PostalAddress
            type:Organization
      name:Monica Castanedes-Casey
      affiliation:
            name:Mayo Clinic Florida
            address:
               name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
               type:PostalAddress
            type:Organization
      name:Jeannie Chew
      affiliation:
            name:Mayo Clinic Florida
            address:
               name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
               type:PostalAddress
            type:Organization
            name:Mayo Clinic College of Medicine
            address:
               name:Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, USA
               type:PostalAddress
            type:Organization
      name:Danielle M. Cosio
      affiliation:
            name:Mayo Clinic Florida
            address:
               name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
               type:PostalAddress
            type:Organization
      name:Marka van Blitterswijk
      affiliation:
            name:Mayo Clinic Florida
            address:
               name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
               type:PostalAddress
            type:Organization
      name:Wing C. Lee
      affiliation:
            name:Mayo Clinic Florida
            address:
               name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
               type:PostalAddress
            type:Organization
      name:Rosa Rademakers
      affiliation:
            name:Mayo Clinic Florida
            address:
               name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
               type:PostalAddress
            type:Organization
      name:Kevin B. Boylan
      affiliation:
            name:Mayo Clinic Florida
            address:
               name:Department of Neurology, Mayo Clinic Florida, Jacksonville, USA
               type:PostalAddress
            type:Organization
      name:Dennis W. Dickson
      affiliation:
            name:Mayo Clinic Florida
            address:
               name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
               type:PostalAddress
            type:Organization
      email:[email protected]
      name:Leonard Petrucelli
      affiliation:
            name:Mayo Clinic Florida
            address:
               name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
      name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
      name:Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, USA
      name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
      name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
      name:Department of Pharmacology, Boston University School of Medicine, Boston, USA
      name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
      name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
      name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
      name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
      name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
      name:Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, USA
      name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
      name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
      name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
      name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
      name:Department of Neurology, Mayo Clinic Florida, Jacksonville, USA
      name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA
      name:Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA

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