Cargando…

Patterns of CAG repeat instability in the central nervous system and periphery in Huntington’s disease and in spinocerebellar ataxia type 1

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Mouro Pinto, Ricardo, Arning, Larissa, Giordano, James V, Razghandi, Pedram, Andrew, Marissa A, Gillis, Tammy, Correia, Kevin, Mysore, Jayalakshmi S, Grote Urtubey, Debora-M, Parwez, Constanze R, von Hein, Sarah M, Clark, H Brent, Nguyen, Huu Phuc, Förster, Eckart, Beller, Allison, Jayadaev, Suman, Keene, C Dirk, Bird, Thomas D, Lucente, Diane, Vonsattel, Jean-Paul, Orr, Harry, Saft, Carsten, Petrasch-Parwez, Elisabeth, Wheeler, Vanessa C
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471505/
https://www.ncbi.nlm.nih.gov/pubmed/32761094
http://dx.doi.org/10.1093/hmg/ddaa139
_version_ 1783578782056054784
author Mouro Pinto, Ricardo
Arning, Larissa
Giordano, James V
Razghandi, Pedram
Andrew, Marissa A
Gillis, Tammy
Correia, Kevin
Mysore, Jayalakshmi S
Grote Urtubey, Debora-M
Parwez, Constanze R
von Hein, Sarah M
Clark, H Brent
Nguyen, Huu Phuc
Förster, Eckart
Beller, Allison
Jayadaev, Suman
Keene, C Dirk
Bird, Thomas D
Lucente, Diane
Vonsattel, Jean-Paul
Orr, Harry
Saft, Carsten
Petrasch-Parwez, Elisabeth
Wheeler, Vanessa C
author_facet Mouro Pinto, Ricardo
Arning, Larissa
Giordano, James V
Razghandi, Pedram
Andrew, Marissa A
Gillis, Tammy
Correia, Kevin
Mysore, Jayalakshmi S
Grote Urtubey, Debora-M
Parwez, Constanze R
von Hein, Sarah M
Clark, H Brent
Nguyen, Huu Phuc
Förster, Eckart
Beller, Allison
Jayadaev, Suman
Keene, C Dirk
Bird, Thomas D
Lucente, Diane
Vonsattel, Jean-Paul
Orr, Harry
Saft, Carsten
Petrasch-Parwez, Elisabeth
Wheeler, Vanessa C
author_sort Mouro Pinto, Ricardo
collection PubMed
description 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.
format Online
Article
Text
id pubmed-7471505
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Oxford University Press
record_format MEDLINE/PubMed
spelling pubmed-74715052020-09-09 Patterns of CAG repeat instability in the central nervous system and periphery in Huntington’s disease and in spinocerebellar ataxia type 1 Mouro Pinto, Ricardo Arning, Larissa Giordano, James V Razghandi, Pedram Andrew, Marissa A Gillis, Tammy Correia, Kevin Mysore, Jayalakshmi S Grote Urtubey, Debora-M Parwez, Constanze R von Hein, Sarah M Clark, H Brent Nguyen, Huu Phuc Förster, Eckart Beller, Allison Jayadaev, Suman Keene, C Dirk Bird, Thomas D Lucente, Diane Vonsattel, Jean-Paul Orr, Harry Saft, Carsten Petrasch-Parwez, Elisabeth Wheeler, Vanessa C Hum Mol Genet General Article 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. Oxford University Press 2020-08-29 2020-07-07 /pmc/articles/PMC7471505/ /pubmed/32761094 http://dx.doi.org/10.1093/hmg/ddaa139 Text en © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle General Article
Mouro Pinto, Ricardo
Arning, Larissa
Giordano, James V
Razghandi, Pedram
Andrew, Marissa A
Gillis, Tammy
Correia, Kevin
Mysore, Jayalakshmi S
Grote Urtubey, Debora-M
Parwez, Constanze R
von Hein, Sarah M
Clark, H Brent
Nguyen, Huu Phuc
Förster, Eckart
Beller, Allison
Jayadaev, Suman
Keene, C Dirk
Bird, Thomas D
Lucente, Diane
Vonsattel, Jean-Paul
Orr, Harry
Saft, Carsten
Petrasch-Parwez, Elisabeth
Wheeler, Vanessa C
Patterns of CAG repeat instability in the central nervous system and periphery in Huntington’s disease and in spinocerebellar ataxia type 1
title Patterns of CAG repeat instability in the central nervous system and periphery in Huntington’s disease and in spinocerebellar ataxia type 1
title_full Patterns of CAG repeat instability in the central nervous system and periphery in Huntington’s disease and in spinocerebellar ataxia type 1
title_fullStr Patterns of CAG repeat instability in the central nervous system and periphery in Huntington’s disease and in spinocerebellar ataxia type 1
title_full_unstemmed Patterns of CAG repeat instability in the central nervous system and periphery in Huntington’s disease and in spinocerebellar ataxia type 1
title_short Patterns of CAG repeat instability in the central nervous system and periphery in Huntington’s disease and in spinocerebellar ataxia type 1
title_sort patterns of cag repeat instability in the central nervous system and periphery in huntington’s disease and in spinocerebellar ataxia type 1
topic General Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471505/
https://www.ncbi.nlm.nih.gov/pubmed/32761094
http://dx.doi.org/10.1093/hmg/ddaa139
work_keys_str_mv AT mouropintoricardo patternsofcagrepeatinstabilityinthecentralnervoussystemandperipheryinhuntingtonsdiseaseandinspinocerebellarataxiatype1
AT arninglarissa patternsofcagrepeatinstabilityinthecentralnervoussystemandperipheryinhuntingtonsdiseaseandinspinocerebellarataxiatype1
AT giordanojamesv patternsofcagrepeatinstabilityinthecentralnervoussystemandperipheryinhuntingtonsdiseaseandinspinocerebellarataxiatype1
AT razghandipedram patternsofcagrepeatinstabilityinthecentralnervoussystemandperipheryinhuntingtonsdiseaseandinspinocerebellarataxiatype1
AT andrewmarissaa patternsofcagrepeatinstabilityinthecentralnervoussystemandperipheryinhuntingtonsdiseaseandinspinocerebellarataxiatype1
AT gillistammy patternsofcagrepeatinstabilityinthecentralnervoussystemandperipheryinhuntingtonsdiseaseandinspinocerebellarataxiatype1
AT correiakevin patternsofcagrepeatinstabilityinthecentralnervoussystemandperipheryinhuntingtonsdiseaseandinspinocerebellarataxiatype1
AT mysorejayalakshmis patternsofcagrepeatinstabilityinthecentralnervoussystemandperipheryinhuntingtonsdiseaseandinspinocerebellarataxiatype1
AT groteurtubeydeboram patternsofcagrepeatinstabilityinthecentralnervoussystemandperipheryinhuntingtonsdiseaseandinspinocerebellarataxiatype1
AT parwezconstanzer patternsofcagrepeatinstabilityinthecentralnervoussystemandperipheryinhuntingtonsdiseaseandinspinocerebellarataxiatype1
AT vonheinsarahm patternsofcagrepeatinstabilityinthecentralnervoussystemandperipheryinhuntingtonsdiseaseandinspinocerebellarataxiatype1
AT clarkhbrent patternsofcagrepeatinstabilityinthecentralnervoussystemandperipheryinhuntingtonsdiseaseandinspinocerebellarataxiatype1
AT nguyenhuuphuc patternsofcagrepeatinstabilityinthecentralnervoussystemandperipheryinhuntingtonsdiseaseandinspinocerebellarataxiatype1
AT forstereckart patternsofcagrepeatinstabilityinthecentralnervoussystemandperipheryinhuntingtonsdiseaseandinspinocerebellarataxiatype1
AT bellerallison patternsofcagrepeatinstabilityinthecentralnervoussystemandperipheryinhuntingtonsdiseaseandinspinocerebellarataxiatype1
AT jayadaevsuman patternsofcagrepeatinstabilityinthecentralnervoussystemandperipheryinhuntingtonsdiseaseandinspinocerebellarataxiatype1
AT keenecdirk patternsofcagrepeatinstabilityinthecentralnervoussystemandperipheryinhuntingtonsdiseaseandinspinocerebellarataxiatype1
AT birdthomasd patternsofcagrepeatinstabilityinthecentralnervoussystemandperipheryinhuntingtonsdiseaseandinspinocerebellarataxiatype1
AT lucentediane patternsofcagrepeatinstabilityinthecentralnervoussystemandperipheryinhuntingtonsdiseaseandinspinocerebellarataxiatype1
AT vonsatteljeanpaul patternsofcagrepeatinstabilityinthecentralnervoussystemandperipheryinhuntingtonsdiseaseandinspinocerebellarataxiatype1
AT orrharry patternsofcagrepeatinstabilityinthecentralnervoussystemandperipheryinhuntingtonsdiseaseandinspinocerebellarataxiatype1
AT saftcarsten patternsofcagrepeatinstabilityinthecentralnervoussystemandperipheryinhuntingtonsdiseaseandinspinocerebellarataxiatype1
AT petraschparwezelisabeth patternsofcagrepeatinstabilityinthecentralnervoussystemandperipheryinhuntingtonsdiseaseandinspinocerebellarataxiatype1
AT wheelervanessac patternsofcagrepeatinstabilityinthecentralnervoussystemandperipheryinhuntingtonsdiseaseandinspinocerebellarataxiatype1