Cargando…
Huntington’s disease blood and brain show a common gene expression pattern and share an immune signature with Alzheimer’s disease
There is widespread transcriptional dysregulation in Huntington’s disease (HD) brain, but analysis is inevitably limited by advanced disease and postmortem changes. However, mutant HTT is ubiquitously expressed and acts systemically, meaning blood, which is readily available and contains cells that...
Autores principales: | , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5359597/ https://www.ncbi.nlm.nih.gov/pubmed/28322270 http://dx.doi.org/10.1038/srep44849 |
_version_ | 1782516408362467328 |
---|---|
author | Hensman Moss, Davina J. Flower, Michael D. Lo, Kitty K. Miller, James R. C. van Ommen, Gert-Jan B. ’t Hoen, Peter A. C. Stone, Timothy C. Guinee, Amelia Langbehn, Douglas R. Jones, Lesley Plagnol, Vincent van Roon-Mom, Willeke M. C. Holmans, Peter Tabrizi, Sarah J. |
author_facet | Hensman Moss, Davina J. Flower, Michael D. Lo, Kitty K. Miller, James R. C. van Ommen, Gert-Jan B. ’t Hoen, Peter A. C. Stone, Timothy C. Guinee, Amelia Langbehn, Douglas R. Jones, Lesley Plagnol, Vincent van Roon-Mom, Willeke M. C. Holmans, Peter Tabrizi, Sarah J. |
author_sort | Hensman Moss, Davina J. |
collection | PubMed |
description | There is widespread transcriptional dysregulation in Huntington’s disease (HD) brain, but analysis is inevitably limited by advanced disease and postmortem changes. However, mutant HTT is ubiquitously expressed and acts systemically, meaning blood, which is readily available and contains cells that are dysfunctional in HD, could act as a surrogate for brain tissue. We conducted an RNA-Seq transcriptomic analysis using whole blood from two HD cohorts, and performed gene set enrichment analysis using public databases and weighted correlation network analysis modules from HD and control brain datasets. We identified dysregulated gene sets in blood that replicated in the independent cohorts, correlated with disease severity, corresponded to the most significantly dysregulated modules in the HD caudate, the most prominently affected brain region, and significantly overlapped with the transcriptional signature of HD myeloid cells. High-throughput sequencing technologies and use of gene sets likely surmounted the limitations of previously inconsistent HD blood expression studies. Our results suggest transcription is disrupted in peripheral cells in HD through mechanisms that parallel those in brain. Immune upregulation in HD overlapped with Alzheimer’s disease, suggesting a common pathogenic mechanism involving macrophage phagocytosis and microglial synaptic pruning, and raises the potential for shared therapeutic approaches. |
format | Online Article Text |
id | pubmed-5359597 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-53595972017-03-22 Huntington’s disease blood and brain show a common gene expression pattern and share an immune signature with Alzheimer’s disease Hensman Moss, Davina J. Flower, Michael D. Lo, Kitty K. Miller, James R. C. van Ommen, Gert-Jan B. ’t Hoen, Peter A. C. Stone, Timothy C. Guinee, Amelia Langbehn, Douglas R. Jones, Lesley Plagnol, Vincent van Roon-Mom, Willeke M. C. Holmans, Peter Tabrizi, Sarah J. Sci Rep Article There is widespread transcriptional dysregulation in Huntington’s disease (HD) brain, but analysis is inevitably limited by advanced disease and postmortem changes. However, mutant HTT is ubiquitously expressed and acts systemically, meaning blood, which is readily available and contains cells that are dysfunctional in HD, could act as a surrogate for brain tissue. We conducted an RNA-Seq transcriptomic analysis using whole blood from two HD cohorts, and performed gene set enrichment analysis using public databases and weighted correlation network analysis modules from HD and control brain datasets. We identified dysregulated gene sets in blood that replicated in the independent cohorts, correlated with disease severity, corresponded to the most significantly dysregulated modules in the HD caudate, the most prominently affected brain region, and significantly overlapped with the transcriptional signature of HD myeloid cells. High-throughput sequencing technologies and use of gene sets likely surmounted the limitations of previously inconsistent HD blood expression studies. Our results suggest transcription is disrupted in peripheral cells in HD through mechanisms that parallel those in brain. Immune upregulation in HD overlapped with Alzheimer’s disease, suggesting a common pathogenic mechanism involving macrophage phagocytosis and microglial synaptic pruning, and raises the potential for shared therapeutic approaches. Nature Publishing Group 2017-03-21 /pmc/articles/PMC5359597/ /pubmed/28322270 http://dx.doi.org/10.1038/srep44849 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Hensman Moss, Davina J. Flower, Michael D. Lo, Kitty K. Miller, James R. C. van Ommen, Gert-Jan B. ’t Hoen, Peter A. C. Stone, Timothy C. Guinee, Amelia Langbehn, Douglas R. Jones, Lesley Plagnol, Vincent van Roon-Mom, Willeke M. C. Holmans, Peter Tabrizi, Sarah J. Huntington’s disease blood and brain show a common gene expression pattern and share an immune signature with Alzheimer’s disease |
title | Huntington’s disease blood and brain show a common gene expression pattern and share an immune signature with Alzheimer’s disease |
title_full | Huntington’s disease blood and brain show a common gene expression pattern and share an immune signature with Alzheimer’s disease |
title_fullStr | Huntington’s disease blood and brain show a common gene expression pattern and share an immune signature with Alzheimer’s disease |
title_full_unstemmed | Huntington’s disease blood and brain show a common gene expression pattern and share an immune signature with Alzheimer’s disease |
title_short | Huntington’s disease blood and brain show a common gene expression pattern and share an immune signature with Alzheimer’s disease |
title_sort | huntington’s disease blood and brain show a common gene expression pattern and share an immune signature with alzheimer’s disease |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5359597/ https://www.ncbi.nlm.nih.gov/pubmed/28322270 http://dx.doi.org/10.1038/srep44849 |
work_keys_str_mv | AT hensmanmossdavinaj huntingtonsdiseasebloodandbrainshowacommongeneexpressionpatternandshareanimmunesignaturewithalzheimersdisease AT flowermichaeld huntingtonsdiseasebloodandbrainshowacommongeneexpressionpatternandshareanimmunesignaturewithalzheimersdisease AT lokittyk huntingtonsdiseasebloodandbrainshowacommongeneexpressionpatternandshareanimmunesignaturewithalzheimersdisease AT millerjamesrc huntingtonsdiseasebloodandbrainshowacommongeneexpressionpatternandshareanimmunesignaturewithalzheimersdisease AT vanommengertjanb huntingtonsdiseasebloodandbrainshowacommongeneexpressionpatternandshareanimmunesignaturewithalzheimersdisease AT thoenpeterac huntingtonsdiseasebloodandbrainshowacommongeneexpressionpatternandshareanimmunesignaturewithalzheimersdisease AT stonetimothyc huntingtonsdiseasebloodandbrainshowacommongeneexpressionpatternandshareanimmunesignaturewithalzheimersdisease AT guineeamelia huntingtonsdiseasebloodandbrainshowacommongeneexpressionpatternandshareanimmunesignaturewithalzheimersdisease AT langbehndouglasr huntingtonsdiseasebloodandbrainshowacommongeneexpressionpatternandshareanimmunesignaturewithalzheimersdisease AT joneslesley huntingtonsdiseasebloodandbrainshowacommongeneexpressionpatternandshareanimmunesignaturewithalzheimersdisease AT plagnolvincent huntingtonsdiseasebloodandbrainshowacommongeneexpressionpatternandshareanimmunesignaturewithalzheimersdisease AT vanroonmomwillekemc huntingtonsdiseasebloodandbrainshowacommongeneexpressionpatternandshareanimmunesignaturewithalzheimersdisease AT holmanspeter huntingtonsdiseasebloodandbrainshowacommongeneexpressionpatternandshareanimmunesignaturewithalzheimersdisease AT tabrizisarahj huntingtonsdiseasebloodandbrainshowacommongeneexpressionpatternandshareanimmunesignaturewithalzheimersdisease |