Patterns of CAG repeat instability in the central nervous system and periphery in Huntington’s disease and in spinocerebellar ataxia type 1
Abstract The expanded HTT CAG repeat causing Huntington’s disease (HD) exhibits somatic expansion proposed to drive the rate of disease onset by eliciting a pathological process that ultimately claims vulnerable cells. To gain insight into somatic expansion in humans, we performed comprehensive quan...
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| Published in | Human molecular genetics Vol. 29; no. 15; pp. 2551 - 2567 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
England
Oxford University Press
29.08.2020
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| Online Access | Get full text |
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| Abstract | Abstract
The expanded HTT CAG repeat causing Huntington’s disease (HD) exhibits somatic expansion proposed to drive the rate of disease onset by eliciting a pathological process that ultimately claims vulnerable cells. To gain insight into somatic expansion in humans, we performed comprehensive quantitative analyses of CAG expansion in ~50 central nervous system (CNS) and peripheral postmortem tissues from seven adult-onset and one juvenile-onset HD individual. We also assessed ATXN1 CAG repeat expansion in brain regions of an individual with a neurologically and pathologically distinct repeat expansion disorder, spinocerebellar ataxia type 1 (SCA1). Our findings reveal similar profiles of tissue instability in all HD individuals, which, notably, were also apparent in the SCA1 individual. CAG expansion was observed in all tissues, but to different degrees, with multiple cortical regions and neostriatum tending to have the greatest instability in the CNS, and liver in the periphery. These patterns indicate different propensities for CAG expansion contributed by disease locus-independent trans-factors and demonstrate that expansion per se is not sufficient to cause cell type or disease-specific pathology. Rather, pathology may reflect distinct toxic processes triggered by different repeat lengths across cell types and diseases. We also find that the HTT CAG length-dependent expansion propensity of an individual is reflected in all tissues and in cerebrospinal fluid. Our data indicate that peripheral cells may be a useful source to measure CAG expansion in biomarker assays for therapeutic efforts, prompting efforts to dissect underlying mechanisms of expansion that may differ between the brain and periphery. |
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| AbstractList | The expanded HTT CAG repeat causing Huntington's disease (HD) exhibits somatic expansion proposed to drive the rate of disease onset by eliciting a pathological process that ultimately claims vulnerable cells. To gain insight into somatic expansion in humans, we performed comprehensive quantitative analyses of CAG expansion in ~50 central nervous system (CNS) and peripheral postmortem tissues from seven adult-onset and one juvenile-onset HD individual. We also assessed ATXN1 CAG repeat expansion in brain regions of an individual with a neurologically and pathologically distinct repeat expansion disorder, spinocerebellar ataxia type 1 (SCA1). Our findings reveal similar profiles of tissue instability in all HD individuals, which, notably, were also apparent in the SCA1 individual. CAG expansion was observed in all tissues, but to different degrees, with multiple cortical regions and neostriatum tending to have the greatest instability in the CNS, and liver in the periphery. These patterns indicate different propensities for CAG expansion contributed by disease locus-independent trans-factors and demonstrate that expansion per se is not sufficient to cause cell type or disease-specific pathology. Rather, pathology may reflect distinct toxic processes triggered by different repeat lengths across cell types and diseases. We also find that the HTT CAG length-dependent expansion propensity of an individual is reflected in all tissues and in cerebrospinal fluid. Our data indicate that peripheral cells may be a useful source to measure CAG expansion in biomarker assays for therapeutic efforts, prompting efforts to dissect underlying mechanisms of expansion that may differ between the brain and periphery.The expanded HTT CAG repeat causing Huntington's disease (HD) exhibits somatic expansion proposed to drive the rate of disease onset by eliciting a pathological process that ultimately claims vulnerable cells. To gain insight into somatic expansion in humans, we performed comprehensive quantitative analyses of CAG expansion in ~50 central nervous system (CNS) and peripheral postmortem tissues from seven adult-onset and one juvenile-onset HD individual. We also assessed ATXN1 CAG repeat expansion in brain regions of an individual with a neurologically and pathologically distinct repeat expansion disorder, spinocerebellar ataxia type 1 (SCA1). Our findings reveal similar profiles of tissue instability in all HD individuals, which, notably, were also apparent in the SCA1 individual. CAG expansion was observed in all tissues, but to different degrees, with multiple cortical regions and neostriatum tending to have the greatest instability in the CNS, and liver in the periphery. These patterns indicate different propensities for CAG expansion contributed by disease locus-independent trans-factors and demonstrate that expansion per se is not sufficient to cause cell type or disease-specific pathology. Rather, pathology may reflect distinct toxic processes triggered by different repeat lengths across cell types and diseases. We also find that the HTT CAG length-dependent expansion propensity of an individual is reflected in all tissues and in cerebrospinal fluid. Our data indicate that peripheral cells may be a useful source to measure CAG expansion in biomarker assays for therapeutic efforts, prompting efforts to dissect underlying mechanisms of expansion that may differ between the brain and periphery. The expanded HTT CAG repeat causing Huntington’s disease (HD) exhibits somatic expansion proposed to drive the rate of disease onset by eliciting a pathological process that ultimately claims vulnerable cells. To gain insight into somatic expansion in humans, we performed comprehensive quantitative analyses of CAG expansion in ~50 central nervous system (CNS) and peripheral postmortem tissues from seven adult-onset and one juvenile-onset HD individual. We also assessed ATXN1 CAG repeat expansion in brain regions of an individual with a neurologically and pathologically distinct repeat expansion disorder, spinocerebellar ataxia type 1 (SCA1). Our findings reveal similar profiles of tissue instability in all HD individuals, which, notably, were also apparent in the SCA1 individual. CAG expansion was observed in all tissues, but to different degrees, with multiple cortical regions and neostriatum tending to have the greatest instability in the CNS, and liver in the periphery. These patterns indicate different propensities for CAG expansion contributed by disease locus-independent trans-factors and demonstrate that expansion per se is not sufficient to cause cell type or disease-specific pathology. Rather, pathology may reflect distinct toxic processes triggered by different repeat lengths across cell types and diseases. We also find that the HTT CAG length-dependent expansion propensity of an individual is reflected in all tissues and in cerebrospinal fluid. Our data indicate that peripheral cells may be a useful source to measure CAG expansion in biomarker assays for therapeutic efforts, prompting efforts to dissect underlying mechanisms of expansion that may differ between the brain and periphery. Abstract The expanded HTT CAG repeat causing Huntington’s disease (HD) exhibits somatic expansion proposed to drive the rate of disease onset by eliciting a pathological process that ultimately claims vulnerable cells. To gain insight into somatic expansion in humans, we performed comprehensive quantitative analyses of CAG expansion in ~50 central nervous system (CNS) and peripheral postmortem tissues from seven adult-onset and one juvenile-onset HD individual. We also assessed ATXN1 CAG repeat expansion in brain regions of an individual with a neurologically and pathologically distinct repeat expansion disorder, spinocerebellar ataxia type 1 (SCA1). Our findings reveal similar profiles of tissue instability in all HD individuals, which, notably, were also apparent in the SCA1 individual. CAG expansion was observed in all tissues, but to different degrees, with multiple cortical regions and neostriatum tending to have the greatest instability in the CNS, and liver in the periphery. These patterns indicate different propensities for CAG expansion contributed by disease locus-independent trans-factors and demonstrate that expansion per se is not sufficient to cause cell type or disease-specific pathology. Rather, pathology may reflect distinct toxic processes triggered by different repeat lengths across cell types and diseases. We also find that the HTT CAG length-dependent expansion propensity of an individual is reflected in all tissues and in cerebrospinal fluid. Our data indicate that peripheral cells may be a useful source to measure CAG expansion in biomarker assays for therapeutic efforts, prompting efforts to dissect underlying mechanisms of expansion that may differ between the brain and periphery. The expanded HTT CAG repeat causing Huntington’s disease (HD) exhibits somatic expansion proposed to drive the rate of disease onset by eliciting a pathological process that ultimately claims vulnerable cells. To gain insight into somatic expansion in humans, we performed comprehensive quantitative analyses of CAG expansion in ~50 central nervous system (CNS) and peripheral postmortem tissues from seven adult-onset and one juvenile-onset HD individual. We also assessed ATXN1 CAG repeat expansion in brain regions of an individual with a neurologically and pathologically distinct repeat expansion disorder, spinocerebellar ataxia type 1 (SCA1). Our findings reveal similar profiles of tissue instability in all HD individuals, which, notably, were also apparent in the SCA1 individual. CAG expansion was observed in all tissues, but to different degrees, with multiple cortical regions and neostriatum tending to have the greatest instability in the CNS, and liver in the periphery. These patterns indicate different propensities for CAG expansion contributed by disease locus-independent trans -factors and demonstrate that expansion per se is not sufficient to cause cell type or disease-specific pathology. Rather, pathology may reflect distinct toxic processes triggered by different repeat lengths across cell types and diseases. We also find that the HTT CAG length-dependent expansion propensity of an individual is reflected in all tissues and in cerebrospinal fluid. Our data indicate that peripheral cells may be a useful source to measure CAG expansion in biomarker assays for therapeutic efforts, prompting efforts to dissect underlying mechanisms of expansion that may differ between the brain and periphery. |
| Author | Lucente, Diane Beller, Allison Keene, C Dirk Orr, Harry Razghandi, Pedram Arning, Larissa Wheeler, Vanessa C Jayadaev, Suman Förster, Eckart Mouro Pinto, Ricardo Saft, Carsten Mysore, Jayalakshmi S Gillis, Tammy Nguyen, Huu Phuc Vonsattel, Jean-Paul Correia, Kevin von Hein, Sarah M Grote Urtubey, Debora-M Parwez, Constanze R Andrew, Marissa A Clark, H Brent Bird, Thomas D Giordano, James V Petrasch-Parwez, Elisabeth |
| AuthorAffiliation | 9 Department of Medicine , University of Washington, Seattle, Washington 98195, USA 11 Department of Pathology and Cell Biology , Columbia University Medical Center and the New York Presbyterian Hospital, New York, NY 10032, USA 5 Department of Neurology , Huntington Centre NRW, St. Josef-Hospital, Ruhr-University Bochum, Bochum 44791, Germany 7 Department of Pathology , University of Washington, Seattle, Washington 98195, USA 6 Department of Laboratory Medicine and Pathology , Institute of Translational Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455, USA 8 Department of Neurology , University of Washington, Seattle, Washington 98195, USA 10 Geriatrics Research Education and Clinical Center , VA Puget Sound Medical Center, Seattle, WA 98108, USA 4 Department of Neuroanatomy and Molecular Brain Research , Institute of Anatomy, Ruhr-University Bochum, Bochum 44780, Germany 3 Department of Human Genetics , Ruhr-University Bochum, Bochum 44780, Germany 2 Department of N |
| AuthorAffiliation_xml | – name: 3 Department of Human Genetics , Ruhr-University Bochum, Bochum 44780, Germany – name: 9 Department of Medicine , University of Washington, Seattle, Washington 98195, USA – name: 7 Department of Pathology , University of Washington, Seattle, Washington 98195, USA – name: 4 Department of Neuroanatomy and Molecular Brain Research , Institute of Anatomy, Ruhr-University Bochum, Bochum 44780, Germany – name: 8 Department of Neurology , University of Washington, Seattle, Washington 98195, USA – name: 1 Molecular Neurogenetics Unit , Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA – name: 6 Department of Laboratory Medicine and Pathology , Institute of Translational Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455, USA – name: 11 Department of Pathology and Cell Biology , Columbia University Medical Center and the New York Presbyterian Hospital, New York, NY 10032, USA – name: 2 Department of Neurology , Harvard Medical School, Boston, MA 02115, USA – name: 10 Geriatrics Research Education and Clinical Center , VA Puget Sound Medical Center, Seattle, WA 98108, USA – name: 5 Department of Neurology , Huntington Centre NRW, St. Josef-Hospital, Ruhr-University Bochum, Bochum 44791, Germany |
| Author_xml | – sequence: 1 givenname: Ricardo surname: Mouro Pinto fullname: Mouro Pinto, Ricardo email: RMOUROPINTO@mgh.harvard.edu organization: Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA – sequence: 2 givenname: Larissa surname: Arning fullname: Arning, Larissa email: Larissa.Arning@ruhr-uni-bochum.de organization: Department of Human Genetics, Ruhr-University Bochum, Bochum 44780, Germany – sequence: 3 givenname: James V surname: Giordano fullname: Giordano, James V email: jvgiorda@eckerd.edu organization: Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA – sequence: 4 givenname: Pedram surname: Razghandi fullname: Razghandi, Pedram email: razghandi.pedram@gmail.com organization: Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA – sequence: 5 givenname: Marissa A surname: Andrew fullname: Andrew, Marissa A email: MANDREW@PARTNERS.ORG organization: Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA – sequence: 6 givenname: Tammy surname: Gillis fullname: Gillis, Tammy email: gillis@helix.mgh.harvard.edu organization: Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA – sequence: 7 givenname: Kevin surname: Correia fullname: Correia, Kevin email: Kevin_Correia@DFCI.HARVARD.EDU organization: Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA – sequence: 8 givenname: Jayalakshmi S surname: Mysore fullname: Mysore, Jayalakshmi S email: SRINIDHI@HELIX.MGH.HARVARD.EDU organization: Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA – sequence: 9 givenname: Debora-M surname: Grote Urtubey fullname: Grote Urtubey, Debora-M email: Debora-Michele.GroteUrtubey@ruhr-uni-bochum.de organization: Department of Human Genetics, Ruhr-University Bochum, Bochum 44780, Germany – sequence: 10 givenname: Constanze R surname: Parwez fullname: Parwez, Constanze R email: Constanze.Parwez@hhu.de organization: Department of Neuroanatomy and Molecular Brain Research, Institute of Anatomy, Ruhr-University Bochum, Bochum 44780, Germany – sequence: 11 givenname: Sarah M surname: von Hein fullname: von Hein, Sarah M email: s.von-hein@klinikum-bochum.de organization: Department of Neurology, Huntington Centre NRW, St. Josef-Hospital, Ruhr-University Bochum, Bochum 44791, Germany – sequence: 12 givenname: H Brent surname: Clark fullname: Clark, H Brent email: clark002@umn.edu organization: Department of Laboratory Medicine and Pathology, Institute of Translational Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455, USA – sequence: 13 givenname: Huu Phuc surname: Nguyen fullname: Nguyen, Huu Phuc email: huu.nguyen-r7w@rub.de organization: Department of Human Genetics, Ruhr-University Bochum, Bochum 44780, Germany – sequence: 14 givenname: Eckart surname: Förster fullname: Förster, Eckart email: Eckart.Foerster@rub.de organization: Department of Neuroanatomy and Molecular Brain Research, Institute of Anatomy, Ruhr-University Bochum, Bochum 44780, Germany – sequence: 15 givenname: Allison surname: Beller fullname: Beller, Allison email: allisonbeller@gmail.com organization: Department of Pathology, University of Washington, Seattle, Washington 98195, USA – sequence: 16 givenname: Suman surname: Jayadaev fullname: Jayadaev, Suman email: sumie@uw.edu organization: Department of Neurology, University of Washington, Seattle, Washington 98195, USA – sequence: 17 givenname: C Dirk surname: Keene fullname: Keene, C Dirk email: cdkeene@uw.edu organization: Department of Pathology, University of Washington, Seattle, Washington 98195, USA – sequence: 18 givenname: Thomas D surname: Bird fullname: Bird, Thomas D email: tomnroz@uw.edu organization: Department of Neurology, University of Washington, Seattle, Washington 98195, USA – sequence: 19 givenname: Diane surname: Lucente fullname: Lucente, Diane email: dlucente@partners.org organization: Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA – sequence: 20 givenname: Jean-Paul surname: Vonsattel fullname: Vonsattel, Jean-Paul email: jgv2001@cumc.columbia.edu organization: Department of Pathology and Cell Biology, Columbia University Medical Center and the New York Presbyterian Hospital, New York, NY 10032, USA – sequence: 21 givenname: Harry surname: Orr fullname: Orr, Harry organization: Department of Laboratory Medicine and Pathology, Institute of Translational Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455, USA – sequence: 22 givenname: Carsten surname: Saft fullname: Saft, Carsten email: Carsten.Saft@ruhr-uni-bochum.de organization: Department of Neurology, Huntington Centre NRW, St. Josef-Hospital, Ruhr-University Bochum, Bochum 44791, Germany – sequence: 23 givenname: Elisabeth surname: Petrasch-Parwez fullname: Petrasch-Parwez, Elisabeth email: elisabeth.petrasch-parwez@rub.de organization: Department of Neuroanatomy and Molecular Brain Research, Institute of Anatomy, Ruhr-University Bochum, Bochum 44780, Germany – sequence: 24 givenname: Vanessa C surname: Wheeler fullname: Wheeler, Vanessa C email: Wheeler@helix.mgh.harvard.edu organization: Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/32761094$$D View this record in MEDLINE/PubMed |
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The expanded HTT CAG repeat causing Huntington’s disease (HD) exhibits somatic expansion proposed to drive the rate of disease onset by eliciting a... The expanded HTT CAG repeat causing Huntington’s disease (HD) exhibits somatic expansion proposed to drive the rate of disease onset by eliciting a... The expanded HTT CAG repeat causing Huntington's disease (HD) exhibits somatic expansion proposed to drive the rate of disease onset by eliciting a... The expanded HTT CAG repeat causing Huntington’s disease (HD) exhibits somatic expansion proposed to drive the rate of disease onset by eliciting a... |
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| Title | Patterns of CAG repeat instability in the central nervous system and periphery in Huntington’s disease and in spinocerebellar ataxia type 1 |
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