Journal Article

DZNE-2022-01420

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Single-nucleus chromatin accessibility profiling highlights distinct astrocyte signatures in progressive supranuclear palsy and corticobasal degeneration.

Briel, N. (First author)DZNE* ; Ruf, V. C. ; Pratsch, K.DZNE* ; Roeber, S. ; Widmann, J.Extern* ; Mielke, J. ; Dorostkar, M. M.Extern* ; Windl, O.Extern* ; Arzberger, T.DZNE* ; Herms, J.DZNE* ; Strübing, F. (Last author)DZNE*

2022
Springer Heidelberg

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Please use a persistent id in citations: doi:10.1007/s00401-022-02483-8

Abstract: Tauopathies such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) exhibit characteristic neuronal and glial inclusions of hyperphosphorylated Tau (pTau). Although the astrocytic pTau phenotype upon neuropathological examination is the most guiding feature in distinguishing both diseases, regulatory mechanisms controlling their transitions into disease-specific states are poorly understood to date. Here, we provide accessible chromatin data of more than 45,000 single nuclei isolated from the frontal cortex of PSP, CBD, and control individuals. We found a strong association of disease-relevant molecular changes with astrocytes and demonstrate that tauopathy-relevant genetic risk variants are tightly linked to astrocytic chromatin accessibility profiles in the brains of PSP and CBD patients. Unlike the established pathogenesis in the secondary tauopathy Alzheimer disease, microglial alterations were relatively sparse. Transcription factor (TF) motif enrichments in pseudotime as well as modeling of the astrocytic TF interplay suggested a common pTau signature for CBD and PSP that is reminiscent of an inflammatory immediate-early response. Nonetheless, machine learning models also predicted discriminatory features, and we observed marked differences in molecular entities related to protein homeostasis between both diseases. Predicted TF involvement was supported by immunofluorescence analyses in postmortem brain tissue for their highly correlated target genes. Collectively, our data expand the current knowledge on risk gene involvement (e.g., MAPT, MAPK8, and NFE2L2) and molecular pathways leading to the phenotypic changes associated with CBD and PSP.

Keyword(s): Astrocytes: pathology (MeSH) ; Chromatin (MeSH) ; Corticobasal Degeneration (MeSH) ; Humans (MeSH) ; Supranuclear Palsy, Progressive: pathology (MeSH) ; Tauopathies: genetics (MeSH) ; Tauopathies: pathology (MeSH) ; tau Proteins: genetics (MeSH) ; tau Proteins: metabolism (MeSH) ; Astrocytes ; Corticobasal degeneration ; Neurodegeneration ; Progressive supranuclear palsy ; Tauopathy ; snATAC-seq

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Contributing Institute(s):

1. Translational Brain Research (AG Herms)
2. Neuropathology / Brainbank (Neuropathology / Brainbank)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2022

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Springer ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 15 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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