PittsburghV1, Main, Exploration, bibRecord, 003E43

Antisense proline-arginine RAN dipeptides linked to C9ORF72-ALS/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death.

Identifieur interne : 003E43 ( Main/Exploration ); précédent : 003E42; suivant : 003E44

Antisense proline-arginine RAN dipeptides linked to C9ORF72-ALS/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death.

Auteurs : Xinmei Wen [États-Unis] ; Wenzhi Tan [États-Unis] ; Thomas Westergard [États-Unis] ; Karthik Krishnamurthy [États-Unis] ; Shashirekha S. Markandaiah [États-Unis] ; Yingxiao Shi [États-Unis] ; Shaoyu Lin [États-Unis] ; Neil A. Shneider [États-Unis] ; John Monaghan [États-Unis] ; Udai B. Pandey [États-Unis] ; Piera Pasinelli [États-Unis] ; Justin K. Ichida [États-Unis] ; Davide Trotti [États-Unis]

Source :

Neuron [ 1097-4199 ] ; 2014.

RBID : pubmed:25521377

Descripteurs français

English descriptors

KwdEn :
- Amyotrophic Lateral Sclerosis (genetics), Amyotrophic Lateral Sclerosis (pathology), Animals, Animals, Genetically Modified, Antisense Elements (Genetics) (genetics), Antisense Elements (Genetics) (toxicity), Arginine, Cell Death (drug effects), Cell Death (genetics), DNA Repeat Expansion (genetics), Dipeptides (toxicity), Drosophila melanogaster, Frontotemporal Dementia (genetics), Frontotemporal Dementia (pathology), Humans, Motor Neurons (drug effects), Motor Neurons (pathology), Neurons (drug effects), Neurons (pathology), Primary Cell Culture, Proline, Protein Aggregation, Pathological, Proteins (genetics), Spinal Cord (metabolism).
MESH :
- chemical , genetics : Antisense Elements (Genetics), Proteins.
- drug effects : Cell Death, Motor Neurons, Neurons.
- genetics : Amyotrophic Lateral Sclerosis, Cell Death, DNA Repeat Expansion, Frontotemporal Dementia.
- metabolism : Spinal Cord.
- pathology : Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Motor Neurons, Neurons.
- chemical , toxicity : Antisense Elements (Genetics), Dipeptides.
- Animals, Animals, Genetically Modified, Arginine, Drosophila melanogaster, Humans, Primary Cell Culture, Proline, Protein Aggregation, Pathological.

Abstract

Expanded GGGGCC (G4C2) nucleotide repeats within the C9ORF72 gene are the most common genetic mutation associated with both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Sense and antisense transcripts of these expansions are translated to form five dipeptide repeat proteins (DRPs). We employed primary cortical and motor neuron cultures, live-cell imaging, and transgenic fly models and found that the arginine-rich dipeptides, in particular Proline-Arginine (PR), are potently neurotoxic. Factors that anticipated their neurotoxicity included aggregation in nucleoli, decreased number of processing bodies, and stress granule formation, implying global translational dysregulation as path accountable for toxicity. Nuclear PR aggregates were also found in human induced motor neurons and postmortem spinal cord tissues from C9ORF72 ALS and ALS/FTD patients. Intronic G4C2 transcripts, but not loss of C9ORF72 protein, are also toxic to motor and cortical neurons. Interestingly, G4C2 transcript-mediated neurotoxicity synergizes with that of PR aggregates, suggesting convergence of mechanisms.

DOI: 10.1016/j.neuron.2014.12.010
PubMed: 25521377

Affiliations:

Le document en format XML

<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Antisense proline-arginine RAN dipeptides linked to C9ORF72-ALS/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death.</title>
<author><name sortKey="Wen, Xinmei" sort="Wen, Xinmei" uniqKey="Wen X" first="Xinmei" last="Wen">Xinmei Wen</name>
<affiliation wicri:level="2"><nlm:affiliation>Frances and Joseph Weinberg Unit for ALS Research, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Frances and Joseph Weinberg Unit for ALS Research, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Tan, Wenzhi" sort="Tan, Wenzhi" uniqKey="Tan W" first="Wenzhi" last="Tan">Wenzhi Tan</name>
<affiliation wicri:level="2"><nlm:affiliation>Frances and Joseph Weinberg Unit for ALS Research, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Frances and Joseph Weinberg Unit for ALS Research, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Westergard, Thomas" sort="Westergard, Thomas" uniqKey="Westergard T" first="Thomas" last="Westergard">Thomas Westergard</name>
<affiliation wicri:level="2"><nlm:affiliation>Frances and Joseph Weinberg Unit for ALS Research, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Frances and Joseph Weinberg Unit for ALS Research, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Krishnamurthy, Karthik" sort="Krishnamurthy, Karthik" uniqKey="Krishnamurthy K" first="Karthik" last="Krishnamurthy">Karthik Krishnamurthy</name>
<affiliation wicri:level="2"><nlm:affiliation>Frances and Joseph Weinberg Unit for ALS Research, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Frances and Joseph Weinberg Unit for ALS Research, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Markandaiah, Shashirekha S" sort="Markandaiah, Shashirekha S" uniqKey="Markandaiah S" first="Shashirekha S" last="Markandaiah">Shashirekha S. Markandaiah</name>
<affiliation wicri:level="2"><nlm:affiliation>Frances and Joseph Weinberg Unit for ALS Research, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Frances and Joseph Weinberg Unit for ALS Research, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Shi, Yingxiao" sort="Shi, Yingxiao" uniqKey="Shi Y" first="Yingxiao" last="Shi">Yingxiao Shi</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, CA 90089, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, CA 90089</wicri:regionArea>
<placeName><region type="state">Californie</region>
<settlement type="city">Los Angeles</settlement>
</placeName>
<orgName type="university">Université de Californie du Sud</orgName>
</affiliation>
</author>
<author><name sortKey="Lin, Shaoyu" sort="Lin, Shaoyu" uniqKey="Lin S" first="Shaoyu" last="Lin">Shaoyu Lin</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, CA 90089, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, CA 90089</wicri:regionArea>
<placeName><region type="state">Californie</region>
<settlement type="city">Los Angeles</settlement>
</placeName>
<orgName type="university">Université de Californie du Sud</orgName>
</affiliation>
</author>
<author><name sortKey="Shneider, Neil A" sort="Shneider, Neil A" uniqKey="Shneider N" first="Neil A" last="Shneider">Neil A. Shneider</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Neurology, The Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, NY 10032, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Neurology, The Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, NY 10032</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Monaghan, John" sort="Monaghan, John" uniqKey="Monaghan J" first="John" last="Monaghan">John Monaghan</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Pediatrics, Child Neurology and Neurobiology, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, One Children's Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pediatrics, Child Neurology and Neurobiology, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, One Children's Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Pandey, Udai B" sort="Pandey, Udai B" uniqKey="Pandey U" first="Udai B" last="Pandey">Udai B. Pandey</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Pediatrics, Child Neurology and Neurobiology, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, One Children's Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pediatrics, Child Neurology and Neurobiology, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, One Children's Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Pasinelli, Piera" sort="Pasinelli, Piera" uniqKey="Pasinelli P" first="Piera" last="Pasinelli">Piera Pasinelli</name>
<affiliation wicri:level="2"><nlm:affiliation>Frances and Joseph Weinberg Unit for ALS Research, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Frances and Joseph Weinberg Unit for ALS Research, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Ichida, Justin K" sort="Ichida, Justin K" uniqKey="Ichida J" first="Justin K" last="Ichida">Justin K. Ichida</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, CA 90089, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, CA 90089</wicri:regionArea>
<placeName><region type="state">Californie</region>
<settlement type="city">Los Angeles</settlement>
</placeName>
<orgName type="university">Université de Californie du Sud</orgName>
</affiliation>
</author>
<author><name sortKey="Trotti, Davide" sort="Trotti, Davide" uniqKey="Trotti D" first="Davide" last="Trotti">Davide Trotti</name>
<affiliation wicri:level="2"><nlm:affiliation>Frances and Joseph Weinberg Unit for ALS Research, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107, USA. Electronic address: davide.trotti@jefferson.edu.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Frances and Joseph Weinberg Unit for ALS Research, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PubMed</idno>
<date when="2014">2014</date>
<idno type="RBID">pubmed:25521377</idno>
<idno type="pmid">25521377</idno>
<idno type="doi">10.1016/j.neuron.2014.12.010</idno>
<idno type="wicri:Area/PubMed/Corpus">000D67</idno>
<idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000D67</idno>
<idno type="wicri:Area/PubMed/Curation">000D64</idno>
<idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000D64</idno>
<idno type="wicri:Area/PubMed/Checkpoint">000D64</idno>
<idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000D64</idno>
<idno type="wicri:Area/Ncbi/Merge">004480</idno>
<idno type="wicri:Area/Ncbi/Curation">004480</idno>
<idno type="wicri:Area/Ncbi/Checkpoint">004480</idno>
<idno type="wicri:Area/Main/Merge">004048</idno>
<idno type="wicri:Area/Main/Curation">003E43</idno>
<idno type="wicri:Area/Main/Exploration">003E43</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en">Antisense proline-arginine RAN dipeptides linked to C9ORF72-ALS/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death.</title>
<author><name sortKey="Wen, Xinmei" sort="Wen, Xinmei" uniqKey="Wen X" first="Xinmei" last="Wen">Xinmei Wen</name>
<affiliation wicri:level="2"><nlm:affiliation>Frances and Joseph Weinberg Unit for ALS Research, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Frances and Joseph Weinberg Unit for ALS Research, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Tan, Wenzhi" sort="Tan, Wenzhi" uniqKey="Tan W" first="Wenzhi" last="Tan">Wenzhi Tan</name>
<affiliation wicri:level="2"><nlm:affiliation>Frances and Joseph Weinberg Unit for ALS Research, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Frances and Joseph Weinberg Unit for ALS Research, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Westergard, Thomas" sort="Westergard, Thomas" uniqKey="Westergard T" first="Thomas" last="Westergard">Thomas Westergard</name>
<affiliation wicri:level="2"><nlm:affiliation>Frances and Joseph Weinberg Unit for ALS Research, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Frances and Joseph Weinberg Unit for ALS Research, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Krishnamurthy, Karthik" sort="Krishnamurthy, Karthik" uniqKey="Krishnamurthy K" first="Karthik" last="Krishnamurthy">Karthik Krishnamurthy</name>
<affiliation wicri:level="2"><nlm:affiliation>Frances and Joseph Weinberg Unit for ALS Research, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Frances and Joseph Weinberg Unit for ALS Research, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Markandaiah, Shashirekha S" sort="Markandaiah, Shashirekha S" uniqKey="Markandaiah S" first="Shashirekha S" last="Markandaiah">Shashirekha S. Markandaiah</name>
<affiliation wicri:level="2"><nlm:affiliation>Frances and Joseph Weinberg Unit for ALS Research, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Frances and Joseph Weinberg Unit for ALS Research, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Shi, Yingxiao" sort="Shi, Yingxiao" uniqKey="Shi Y" first="Yingxiao" last="Shi">Yingxiao Shi</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, CA 90089, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, CA 90089</wicri:regionArea>
<placeName><region type="state">Californie</region>
<settlement type="city">Los Angeles</settlement>
</placeName>
<orgName type="university">Université de Californie du Sud</orgName>
</affiliation>
</author>
<author><name sortKey="Lin, Shaoyu" sort="Lin, Shaoyu" uniqKey="Lin S" first="Shaoyu" last="Lin">Shaoyu Lin</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, CA 90089, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, CA 90089</wicri:regionArea>
<placeName><region type="state">Californie</region>
<settlement type="city">Los Angeles</settlement>
</placeName>
<orgName type="university">Université de Californie du Sud</orgName>
</affiliation>
</author>
<author><name sortKey="Shneider, Neil A" sort="Shneider, Neil A" uniqKey="Shneider N" first="Neil A" last="Shneider">Neil A. Shneider</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Neurology, The Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, NY 10032, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Neurology, The Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, NY 10032</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Monaghan, John" sort="Monaghan, John" uniqKey="Monaghan J" first="John" last="Monaghan">John Monaghan</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Pediatrics, Child Neurology and Neurobiology, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, One Children's Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pediatrics, Child Neurology and Neurobiology, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, One Children's Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Pandey, Udai B" sort="Pandey, Udai B" uniqKey="Pandey U" first="Udai B" last="Pandey">Udai B. Pandey</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Pediatrics, Child Neurology and Neurobiology, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, One Children's Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pediatrics, Child Neurology and Neurobiology, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, One Children's Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Pasinelli, Piera" sort="Pasinelli, Piera" uniqKey="Pasinelli P" first="Piera" last="Pasinelli">Piera Pasinelli</name>
<affiliation wicri:level="2"><nlm:affiliation>Frances and Joseph Weinberg Unit for ALS Research, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Frances and Joseph Weinberg Unit for ALS Research, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Ichida, Justin K" sort="Ichida, Justin K" uniqKey="Ichida J" first="Justin K" last="Ichida">Justin K. Ichida</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, CA 90089, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, CA 90089</wicri:regionArea>
<placeName><region type="state">Californie</region>
<settlement type="city">Los Angeles</settlement>
</placeName>
<orgName type="university">Université de Californie du Sud</orgName>
</affiliation>
</author>
<author><name sortKey="Trotti, Davide" sort="Trotti, Davide" uniqKey="Trotti D" first="Davide" last="Trotti">Davide Trotti</name>
<affiliation wicri:level="2"><nlm:affiliation>Frances and Joseph Weinberg Unit for ALS Research, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107, USA. Electronic address: davide.trotti@jefferson.edu.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Frances and Joseph Weinberg Unit for ALS Research, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107</wicri:regionArea>
<placeName><region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
</author>
</analytic>
<series><title level="j">Neuron</title>
<idno type="eISSN">1097-4199</idno>
<imprint><date when="2014" type="published">2014</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amyotrophic Lateral Sclerosis (genetics)</term>
<term>Amyotrophic Lateral Sclerosis (pathology)</term>
<term>Animals</term>
<term>Animals, Genetically Modified</term>
<term>Antisense Elements (Genetics) (genetics)</term>
<term>Antisense Elements (Genetics) (toxicity)</term>
<term>Arginine</term>
<term>Cell Death (drug effects)</term>
<term>Cell Death (genetics)</term>
<term>DNA Repeat Expansion (genetics)</term>
<term>Dipeptides (toxicity)</term>
<term>Drosophila melanogaster</term>
<term>Frontotemporal Dementia (genetics)</term>
<term>Frontotemporal Dementia (pathology)</term>
<term>Humans</term>
<term>Motor Neurons (drug effects)</term>
<term>Motor Neurons (pathology)</term>
<term>Neurons (drug effects)</term>
<term>Neurons (pathology)</term>
<term>Primary Cell Culture</term>
<term>Proline</term>
<term>Protein Aggregation, Pathological</term>
<term>Proteins (genetics)</term>
<term>Spinal Cord (metabolism)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Agrégation pathologique de protéines</term>
<term>Animal génétiquement modifié</term>
<term>Animaux</term>
<term>Arginine</term>
<term>Culture primaire de cellules</term>
<term>Dipeptides (toxicité)</term>
<term>Drosophila melanogaster</term>
<term>Démence frontotemporale (anatomopathologie)</term>
<term>Démence frontotemporale (génétique)</term>
<term>Expansion de séquence répétée de l'ADN (génétique)</term>
<term>Humains</term>
<term>Moelle spinale (métabolisme)</term>
<term>Mort cellulaire ()</term>
<term>Mort cellulaire (génétique)</term>
<term>Motoneurones ()</term>
<term>Motoneurones (anatomopathologie)</term>
<term>Neurones ()</term>
<term>Neurones (anatomopathologie)</term>
<term>Proline</term>
<term>Protéines (génétique)</term>
<term>Sclérose latérale amyotrophique (anatomopathologie)</term>
<term>Sclérose latérale amyotrophique (génétique)</term>
<term>Éléments antisens (génétique) (génétique)</term>
<term>Éléments antisens (génétique) (toxicité)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Antisense Elements (Genetics)</term>
<term>Proteins</term>
</keywords>
<keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Démence frontotemporale</term>
<term>Motoneurones</term>
<term>Neurones</term>
<term>Sclérose latérale amyotrophique</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Cell Death</term>
<term>Motor Neurons</term>
<term>Neurons</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Amyotrophic Lateral Sclerosis</term>
<term>Cell Death</term>
<term>DNA Repeat Expansion</term>
<term>Frontotemporal Dementia</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Démence frontotemporale</term>
<term>Expansion de séquence répétée de l'ADN</term>
<term>Mort cellulaire</term>
<term>Protéines</term>
<term>Sclérose latérale amyotrophique</term>
<term>Éléments antisens (génétique)</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Spinal Cord</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Moelle spinale</term>
</keywords>
<keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Amyotrophic Lateral Sclerosis</term>
<term>Frontotemporal Dementia</term>
<term>Motor Neurons</term>
<term>Neurons</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="toxicity" xml:lang="en"><term>Antisense Elements (Genetics)</term>
<term>Dipeptides</term>
</keywords>
<keywords scheme="MESH" qualifier="toxicité" xml:lang="fr"><term>Dipeptides</term>
<term>Éléments antisens (génétique)</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Animals, Genetically Modified</term>
<term>Arginine</term>
<term>Drosophila melanogaster</term>
<term>Humans</term>
<term>Primary Cell Culture</term>
<term>Proline</term>
<term>Protein Aggregation, Pathological</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Agrégation pathologique de protéines</term>
<term>Animal génétiquement modifié</term>
<term>Animaux</term>
<term>Arginine</term>
<term>Culture primaire de cellules</term>
<term>Drosophila melanogaster</term>
<term>Humains</term>
<term>Mort cellulaire</term>
<term>Motoneurones</term>
<term>Neurones</term>
<term>Proline</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">Expanded GGGGCC (G4C2) nucleotide repeats within the C9ORF72 gene are the most common genetic mutation associated with both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Sense and antisense transcripts of these expansions are translated to form five dipeptide repeat proteins (DRPs). We employed primary cortical and motor neuron cultures, live-cell imaging, and transgenic fly models and found that the arginine-rich dipeptides, in particular Proline-Arginine (PR), are potently neurotoxic. Factors that anticipated their neurotoxicity included aggregation in nucleoli, decreased number of processing bodies, and stress granule formation, implying global translational dysregulation as path accountable for toxicity. Nuclear PR aggregates were also found in human induced motor neurons and postmortem spinal cord tissues from C9ORF72 ALS and ALS/FTD patients. Intronic G4C2 transcripts, but not loss of C9ORF72 protein, are also toxic to motor and cortical neurons. Interestingly, G4C2 transcript-mediated neurotoxicity synergizes with that of PR aggregates, suggesting convergence of mechanisms.</div>
</front>
</TEI>
<affiliations><list><country><li>États-Unis</li>
</country>
<region><li>Californie</li>
<li>Pennsylvanie</li>
<li>État de New York</li>
</region>
<settlement><li>Los Angeles</li>
</settlement>
<orgName><li>Université de Californie du Sud</li>
</orgName>
</list>
<tree><country name="États-Unis"><region name="Pennsylvanie"><name sortKey="Wen, Xinmei" sort="Wen, Xinmei" uniqKey="Wen X" first="Xinmei" last="Wen">Xinmei Wen</name>
</region>
<name sortKey="Ichida, Justin K" sort="Ichida, Justin K" uniqKey="Ichida J" first="Justin K" last="Ichida">Justin K. Ichida</name>
<name sortKey="Krishnamurthy, Karthik" sort="Krishnamurthy, Karthik" uniqKey="Krishnamurthy K" first="Karthik" last="Krishnamurthy">Karthik Krishnamurthy</name>
<name sortKey="Lin, Shaoyu" sort="Lin, Shaoyu" uniqKey="Lin S" first="Shaoyu" last="Lin">Shaoyu Lin</name>
<name sortKey="Markandaiah, Shashirekha S" sort="Markandaiah, Shashirekha S" uniqKey="Markandaiah S" first="Shashirekha S" last="Markandaiah">Shashirekha S. Markandaiah</name>
<name sortKey="Monaghan, John" sort="Monaghan, John" uniqKey="Monaghan J" first="John" last="Monaghan">John Monaghan</name>
<name sortKey="Pandey, Udai B" sort="Pandey, Udai B" uniqKey="Pandey U" first="Udai B" last="Pandey">Udai B. Pandey</name>
<name sortKey="Pasinelli, Piera" sort="Pasinelli, Piera" uniqKey="Pasinelli P" first="Piera" last="Pasinelli">Piera Pasinelli</name>
<name sortKey="Shi, Yingxiao" sort="Shi, Yingxiao" uniqKey="Shi Y" first="Yingxiao" last="Shi">Yingxiao Shi</name>
<name sortKey="Shneider, Neil A" sort="Shneider, Neil A" uniqKey="Shneider N" first="Neil A" last="Shneider">Neil A. Shneider</name>
<name sortKey="Tan, Wenzhi" sort="Tan, Wenzhi" uniqKey="Tan W" first="Wenzhi" last="Tan">Wenzhi Tan</name>
<name sortKey="Trotti, Davide" sort="Trotti, Davide" uniqKey="Trotti D" first="Davide" last="Trotti">Davide Trotti</name>
<name sortKey="Westergard, Thomas" sort="Westergard, Thomas" uniqKey="Westergard T" first="Thomas" last="Westergard">Thomas Westergard</name>
</country>
</tree>
</affiliations>
</record>

Pour manipuler ce document sous Unix (Dilib)

EXPLOR_STEP=$WICRI_ROOT/Wicri/Amérique/explor/PittsburghV1/Data/Main/Exploration

HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 003E43 | SxmlIndent | more

HfdSelect -h $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd -nk 003E43 | SxmlIndent | more

Pour mettre un lien sur cette page dans le réseau Wicri

{{Explor lien
   |wiki=    Wicri/Amérique
   |area=    PittsburghV1
   |flux=    Main
   |étape=   Exploration
   |type=    RBID
   |clé=     pubmed:25521377
   |texte=   Antisense proline-arginine RAN dipeptides linked to C9ORF72-ALS/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death.
}}

Pour générer des pages wiki

HfdIndexSelect -h $EXPLOR_AREA/Data/Main/Exploration/RBID.i   -Sk "pubmed:25521377" \
       | HfdSelect -Kh $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd   \
       | NlmPubMed2Wicri -a PittsburghV1

This area was generated with Dilib version V0.6.38.
Data generation: Fri Jun 18 17:37:45 2021. Site generation: Fri Jun 18 18:15:47 2021

Serveur d'exploration sur Pittsburgh

Antisense proline-arginine RAN dipeptides linked to C9ORF72-ALS/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death.

Antisense proline-arginine RAN dipeptides linked to C9ORF72-ALS/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death.

Source :

Descripteurs français

English descriptors

Abstract

Links toward previous steps (curation, corpus...)

Le document en format XML

Pour manipuler ce document sous Unix (Dilib)

Pour mettre un lien sur cette page dans le réseau Wicri

Pour générer des pages wiki

	Serveur d'exploration sur Pittsburgh
	Attention, ce site est en cours de développement ! Attention, site généré par des moyens informatiques à partir de corpus bruts. Les informations ne sont donc pas validées.