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Open Access 01-11-2018 | Original Paper

Divergent brain gene expression patterns associate with distinct cell-specific tau neuropathology traits in progressive supranuclear palsy

Authors: Mariet Allen, Xue Wang, Daniel J. Serie, Samantha L. Strickland, Jeremy D. Burgess, Shunsuke Koga, Curtis S. Younkin, Thuy T. Nguyen, Kimberly G. Malphrus, Sarah J. Lincoln, Melissa Alamprese, Kuixi Zhu, Rui Chang, Minerva M. Carrasquillo, Naomi Kouri, Melissa E. Murray, Joseph S. Reddy, Cory Funk, Nathan D. Price, Todd E. Golde, Steven G. Younkin, Yan W. Asmann, Julia E. Crook, Dennis W. Dickson, Nilüfer Ertekin-Taner

Published in: Acta Neuropathologica | Issue 5/2018

Abstract

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.

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Title: Divergent brain gene expression patterns associate with distinct cell-specific tau neuropathology traits in progressive supranuclear palsy
Authors: Mariet Allen
Xue Wang
Daniel J. Serie
Samantha L. Strickland
Jeremy D. Burgess
Shunsuke Koga
Curtis S. Younkin
Thuy T. Nguyen
Kimberly G. Malphrus
Sarah J. Lincoln
Melissa Alamprese
Kuixi Zhu
Rui Chang
Minerva M. Carrasquillo
Naomi Kouri
Melissa E. Murray
Joseph S. Reddy
Cory Funk
Nathan D. Price
Todd E. Golde
Steven G. Younkin
Yan W. Asmann
Julia E. Crook
Dennis W. Dickson
Nilüfer Ertekin-Taner
Publication date: 01-11-2018
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 5/2018
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-018-1900-5

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Divergent brain gene expression patterns associate with distinct cell-specific tau neuropathology traits in progressive supranuclear palsy

Abstract

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

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