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000165111 1001_ $$0P:(DE-2719)9001545$$aBriel, Nils$$b0$$eFirst author$$udzne
000165111 245__ $$aSingle-nucleus chromatin accessibility profiling highlights distinct astrocyte signatures in progressive supranuclear palsy and corticobasal degeneration.
000165111 260__ $$aHeidelberg$$bSpringer$$c2022
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000165111 520__ $$aTauopathies 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.
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000165111 650_7 $$2Other$$aAstrocytes
000165111 650_7 $$2Other$$aCorticobasal degeneration
000165111 650_7 $$2Other$$aNeurodegeneration
000165111 650_7 $$2Other$$aProgressive supranuclear palsy
000165111 650_7 $$2Other$$aTauopathy
000165111 650_7 $$2Other$$asnATAC-seq
000165111 650_2 $$2MeSH$$aAstrocytes: pathology
000165111 650_2 $$2MeSH$$aChromatin
000165111 650_2 $$2MeSH$$aCorticobasal Degeneration
000165111 650_2 $$2MeSH$$aHumans
000165111 650_2 $$2MeSH$$aSupranuclear Palsy, Progressive: pathology
000165111 650_2 $$2MeSH$$aTauopathies: genetics
000165111 650_2 $$2MeSH$$aTauopathies: pathology
000165111 650_2 $$2MeSH$$atau Proteins: genetics
000165111 650_2 $$2MeSH$$atau Proteins: metabolism
000165111 7001_ $$aRuf, Viktoria C$$b1
000165111 7001_ $$0P:(DE-2719)2812307$$aPratsch, Katrin$$b2$$udzne
000165111 7001_ $$aRoeber, Sigrun$$b3
000165111 7001_ $$0P:(DE-2719)9000813$$aWidmann, Jeannine$$b4$$udzne
000165111 7001_ $$aMielke, Janina$$b5
000165111 7001_ $$0P:(DE-2719)2812547$$aDorostkar, Mario Manucehr$$b6$$udzne
000165111 7001_ $$0P:(DE-2719)2812263$$aWindl, Otto$$b7$$udzne
000165111 7001_ $$0P:(DE-2719)2811333$$aArzberger, Thomas$$b8$$udzne
000165111 7001_ $$0P:(DE-2719)2810441$$aHerms, Jochen$$b9$$udzne
000165111 7001_ $$0P:(DE-2719)2813904$$aStrübing, Felix$$b10$$eLast author$$udzne
000165111 773__ $$0PERI:(DE-600)1458410-4$$a10.1007/s00401-022-02483-8$$gVol. 144, no. 4, p. 615 - 635$$n4$$p615 - 635$$tActa neuropathologica$$v144$$x0001-6322$$y2022
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