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Divergent brain gene expression patterns associate with distinct cell-specific tau neuropathology traits in progressive supranuclear palsy
Progressive supranuclear palsy (PSP) is a neurodegenerative parkinsonian disorder characterized by tau pathology in neurons and glial cells. Transcriptional regulation has been implicated as a potential mechanism in conferring disease risk and neuropathology for some PSP genetic risk variants. Howev...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208732/ https://www.ncbi.nlm.nih.gov/pubmed/30136084 http://dx.doi.org/10.1007/s00401-018-1900-5 |
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author | Allen, Mariet Wang, Xue Serie, Daniel J. Strickland, Samantha L. Burgess, Jeremy D. Koga, Shunsuke Younkin, Curtis S. Nguyen, Thuy T. Malphrus, Kimberly G. Lincoln, Sarah J. Alamprese, Melissa Zhu, Kuixi Chang, Rui Carrasquillo, Minerva M. Kouri, Naomi Murray, Melissa E. Reddy, Joseph S. Funk, Cory Price, Nathan D. Golde, Todd E. Younkin, Steven G. Asmann, Yan W. Crook, Julia E. Dickson, Dennis W. Ertekin-Taner, Nilüfer |
author_facet | Allen, Mariet Wang, Xue Serie, Daniel J. Strickland, Samantha L. Burgess, Jeremy D. Koga, Shunsuke Younkin, Curtis S. Nguyen, Thuy T. Malphrus, Kimberly G. Lincoln, Sarah J. Alamprese, Melissa Zhu, Kuixi Chang, Rui Carrasquillo, Minerva M. Kouri, Naomi Murray, Melissa E. Reddy, Joseph S. Funk, Cory Price, Nathan D. Golde, Todd E. Younkin, Steven G. Asmann, Yan W. Crook, Julia E. Dickson, Dennis W. Ertekin-Taner, Nilüfer |
author_sort | Allen, Mariet |
collection | PubMed |
description | Progressive supranuclear palsy (PSP) is a neurodegenerative parkinsonian disorder characterized by tau pathology in neurons and glial cells. Transcriptional regulation has been implicated as a potential mechanism in conferring disease risk and neuropathology for some PSP genetic risk variants. However, the role of transcriptional changes as potential drivers of distinct cell-specific tau lesions has not been explored. In this study, we integrated brain gene expression measurements, quantitative neuropathology traits and genome-wide genotypes from 268 autopsy-confirmed PSP patients to identify transcriptional associations with unique cell-specific tau pathologies. We provide individual transcript and transcriptional network associations for quantitative oligodendroglial (coiled bodies = CB), neuronal (neurofibrillary tangles = NFT), astrocytic (tufted astrocytes = TA) tau pathology, and tau threads and genomic annotations of these findings. We identified divergent patterns of transcriptional associations for the distinct tau lesions, with the neuronal and astrocytic neuropathologies being the most different. We determined that NFT are positively associated with a brain co-expression network enriched for synaptic and PSP candidate risk genes, whereas TA are positively associated with a microglial gene-enriched immune network. In contrast, TA is negatively associated with synaptic and NFT with immune system transcripts. Our findings have implications for the diverse molecular mechanisms that underlie cell-specific vulnerability and disease risk in PSP. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00401-018-1900-5) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6208732 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-62087322018-11-09 Divergent brain gene expression patterns associate with distinct cell-specific tau neuropathology traits in progressive supranuclear palsy Allen, Mariet Wang, Xue Serie, Daniel J. Strickland, Samantha L. Burgess, Jeremy D. Koga, Shunsuke Younkin, Curtis S. Nguyen, Thuy T. Malphrus, Kimberly G. Lincoln, Sarah J. Alamprese, Melissa Zhu, Kuixi Chang, Rui Carrasquillo, Minerva M. Kouri, Naomi Murray, Melissa E. Reddy, Joseph S. Funk, Cory Price, Nathan D. Golde, Todd E. Younkin, Steven G. Asmann, Yan W. Crook, Julia E. Dickson, Dennis W. Ertekin-Taner, Nilüfer Acta Neuropathol Original Paper Progressive supranuclear palsy (PSP) is a neurodegenerative parkinsonian disorder characterized by tau pathology in neurons and glial cells. Transcriptional regulation has been implicated as a potential mechanism in conferring disease risk and neuropathology for some PSP genetic risk variants. However, the role of transcriptional changes as potential drivers of distinct cell-specific tau lesions has not been explored. In this study, we integrated brain gene expression measurements, quantitative neuropathology traits and genome-wide genotypes from 268 autopsy-confirmed PSP patients to identify transcriptional associations with unique cell-specific tau pathologies. We provide individual transcript and transcriptional network associations for quantitative oligodendroglial (coiled bodies = CB), neuronal (neurofibrillary tangles = NFT), astrocytic (tufted astrocytes = TA) tau pathology, and tau threads and genomic annotations of these findings. We identified divergent patterns of transcriptional associations for the distinct tau lesions, with the neuronal and astrocytic neuropathologies being the most different. We determined that NFT are positively associated with a brain co-expression network enriched for synaptic and PSP candidate risk genes, whereas TA are positively associated with a microglial gene-enriched immune network. In contrast, TA is negatively associated with synaptic and NFT with immune system transcripts. Our findings have implications for the diverse molecular mechanisms that underlie cell-specific vulnerability and disease risk in PSP. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00401-018-1900-5) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2018-08-22 2018 /pmc/articles/PMC6208732/ /pubmed/30136084 http://dx.doi.org/10.1007/s00401-018-1900-5 Text en © The Author(s) 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. |
spellingShingle | Original Paper Allen, Mariet Wang, Xue Serie, Daniel J. Strickland, Samantha L. Burgess, Jeremy D. Koga, Shunsuke Younkin, Curtis S. Nguyen, Thuy T. Malphrus, Kimberly G. Lincoln, Sarah J. Alamprese, Melissa Zhu, Kuixi Chang, Rui Carrasquillo, Minerva M. Kouri, Naomi Murray, Melissa E. Reddy, Joseph S. Funk, Cory Price, Nathan D. Golde, Todd E. Younkin, Steven G. Asmann, Yan W. Crook, Julia E. Dickson, Dennis W. Ertekin-Taner, Nilüfer Divergent brain gene expression patterns associate with distinct cell-specific tau neuropathology traits in progressive supranuclear palsy |
title | Divergent brain gene expression patterns associate with distinct cell-specific tau neuropathology traits in progressive supranuclear palsy |
title_full | Divergent brain gene expression patterns associate with distinct cell-specific tau neuropathology traits in progressive supranuclear palsy |
title_fullStr | Divergent brain gene expression patterns associate with distinct cell-specific tau neuropathology traits in progressive supranuclear palsy |
title_full_unstemmed | Divergent brain gene expression patterns associate with distinct cell-specific tau neuropathology traits in progressive supranuclear palsy |
title_short | Divergent brain gene expression patterns associate with distinct cell-specific tau neuropathology traits in progressive supranuclear palsy |
title_sort | divergent brain gene expression patterns associate with distinct cell-specific tau neuropathology traits in progressive supranuclear palsy |
topic | Original Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208732/ https://www.ncbi.nlm.nih.gov/pubmed/30136084 http://dx.doi.org/10.1007/s00401-018-1900-5 |
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