TY - JOUR
T1 - Divergent brain gene expression patterns associate with distinct cell-specific tau neuropathology traits in progressive supranuclear palsy
AU - Allen, Mariet
AU - Wang, Xue
AU - Serie, Daniel J.
AU - Strickland, Samantha L.
AU - Burgess, Jeremy D.
AU - Koga, Shunsuke
AU - Younkin, Curtis S.
AU - Nguyen, Thuy T.
AU - Malphrus, Kimberly G.
AU - Lincoln, Sarah J.
AU - Alamprese, Melissa
AU - Zhu, Kuixi
AU - Chang, Rui
AU - Carrasquillo, Minerva M.
AU - Kouri, Naomi
AU - Murray, Melissa E.
AU - Reddy, Joseph S.
AU - Funk, Cory
AU - Price, Nathan D.
AU - Golde, Todd E.
AU - Younkin, Steven G.
AU - Asmann, Yan W.
AU - Crook, Julia E.
AU - Dickson, Dennis W.
AU - Ertekin-Taner, Nilüfer
PY - 2018/11/1
Y1 - 2018/11/1
N2 - 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.
AB - 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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U2 - 10.1007/s00401-018-1900-5
DO - 10.1007/s00401-018-1900-5
M3 - Article
C2 - 30136084
AN - SCOPUS:85052288161
VL - 136
SP - 709
EP - 727
JO - Acta Neuropathologica
JF - Acta Neuropathologica
SN - 0001-6322
IS - 5
ER -