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

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. GoldeSteven G. Younkin, Yan W. Asmann, Julia E. Crook, Dennis W. Dickson, Nilüfer Ertekin-Taner

Research output: Contribution to journalArticle

10 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)709-727
Number of pages19
JournalActa neuropathologica
Volume136
Issue number5
DOIs
StatePublished - Nov 1 2018

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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    Allen, M., Wang, X., Serie, D. J., Strickland, S. L., Burgess, J. D., Koga, S., Younkin, C. S., Nguyen, T. T., Malphrus, K. G., Lincoln, S. J., Alamprese, M., Zhu, K., Chang, R., Carrasquillo, M. M., Kouri, N., Murray, M. E., Reddy, J. S., Funk, C., Price, N. D., ... Ertekin-Taner, N. (2018). Divergent brain gene expression patterns associate with distinct cell-specific tau neuropathology traits in progressive supranuclear palsy. Acta neuropathologica, 136(5), 709-727. https://doi.org/10.1007/s00401-018-1900-5