Journal Article

DZNE-2020-06832

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Stroke target identification guided by astrocyte transcriptome analysis.

Rakers, C. (First author)DZNE* ; Schleif, M.DZNE* ; Blank, N.DZNE* ; Matušková, H.DZNE* ; Ulas, T. ; Händler, K. ; Torres, S. V. ; Schumacher, T.DZNE* ; Tai, K.DZNE* ; Schultze, J. L.DZNE* ; Jackson, W. S.DZNE* ; Petzold, G. C. J. P. (Last author)DZNE*

2019
Wiley-Liss Bognor Regis [u.a.]

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Please use a persistent id in citations: doi:10.1002/glia.23544

Abstract: Astrocytes support normal brain function, but may also contribute to neurodegeneration when they become reactive under pathological conditions such as stroke. However, the molecular underpinnings of this context-dependent interplay between beneficial and detrimental properties in reactive astrogliosis have remained incompletely understood. Therefore, using the RiboTag technique, we immunopurified translating mRNAs specifically from astrocytes 72 hr after transient middle cerebral artery occlusion in mice (tMCAO), thereby generating a stroke-specific astroglial translatome database. We found that compared to control brains, reactive astrocytes after tMCAO show an enrichment of transcripts linked to the A2 phenotype, which has been associated with neuroprotection. However, we found that astrocytes also upregulate a large number of potentially neurotoxic genes. In total, we identified the differential expression of 1,003 genes and 38 transcription factors, of which Stat3, Sp1, and Spi1 were the most prominent. To further explore the effects of Stat3-mediated pathways on stroke pathogenesis, we subjected mice with an astrocyte-specific conditional deletion of Stat3 to tMCAO, and found that these mice have reduced stroke volume and improved motor outcome 72 hr after focal ischemia. Taken together, our study extends the emerging database of novel astrocyte-specific targets for stroke therapy, and supports the role of astrocytes as critical safeguards of brain function in health and disease.

Keyword(s): Animals (MeSH) ; Astrocytes: metabolism (MeSH) ; Computational Biology (MeSH) ; Connexin 43: genetics (MeSH) ; Connexin 43: metabolism (MeSH) ; Disease Models, Animal (MeSH) ; Female (MeSH) ; Galectin 3: genetics (MeSH) ; Galectin 3: metabolism (MeSH) ; Gene Expression Profiling: methods (MeSH) ; Gene Expression Regulation: genetics (MeSH) ; Immunoprecipitation (MeSH) ; Infarction, Middle Cerebral Artery: pathology (MeSH) ; Infarction, Middle Cerebral Artery: physiopathology (MeSH) ; Lipocalin-2: genetics (MeSH) ; Lipocalin-2: metabolism (MeSH) ; Luminescent Proteins: genetics (MeSH) ; Luminescent Proteins: metabolism (MeSH) ; Male (MeSH) ; Mice (MeSH) ; Mice, Inbred C57BL (MeSH) ; Mice, Transgenic (MeSH) ; Nerve Tissue Proteins: metabolism (MeSH) ; Rhombencephalon: pathology (MeSH) ; Rotarod Performance Test (MeSH) ; STAT3 Transcription Factor: genetics (MeSH) ; STAT3 Transcription Factor: metabolism (MeSH) ; Connexin 43 ; Galectin 3 ; Lipocalin-2 ; Luminescent Proteins ; Nerve Tissue Proteins ; STAT3 Transcription Factor ; Stat3 protein, mouse

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Contributing Institute(s):

1. Vascular Neurology (AG Petzold)
2. Selective Vulnerability of Neurodegenerative Diseases (AG Jackson)
3. Regulatory RNA-protein interaction in neurodegenerative diseases (AG Krauß)
4. Clinical Single Cell Omics (CSCO) / Systems Medicine (AG Schultze)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)
2. 344 - Clinical and Health Care Research (POF3-344) (POF3-344)

Appears in the scientific report 2019

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; IF >= 5 ; JCR ; Nationallizenz ; SCOPUS ; Web of Science Core Collection

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