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  Neural metabolic imbalance induced by MOF dysfunction triggers pericyte activation and breakdown of vasculature

Sheikh, B. N., Guhathakurta, S., Tsang, T. H., Schwabenland, M., Renschler, G. V., Herquel, B., et al. (2020). Neural metabolic imbalance induced by MOF dysfunction triggers pericyte activation and breakdown of vasculature. Nature Cell Biology, 22, 828-841. doi:org/10.1038/s41556-020-0526-8.

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Item Permalink: https://hdl.handle.net/21.11116/0000-0006-8F81-7 Version Permalink: https://hdl.handle.net/21.11116/0000-0008-7FCC-5
Genre: Journal Article

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https://www.nature.com/articles/s41556-020-0526-8 (Publisher version)
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 Creators:
Sheikh, Bilal N.1, Author
Guhathakurta, Sukanya1, Author           
Tsang, Tsz Hong1, Author
Schwabenland, Marius2, Author
Renschler, Gina Vanessa1, Author           
Herquel, Benjamin1, Author           
Bhardwaj, Vivek1, Author
Holz, Herbert1, Author           
Stehle, Thomas1, Author           
Bondareva, Olga2, Author
Aizarni, Nadim1, Author
Mossad, Omar2, Author
Kretz, Oliver2, Author
Reichardt, Wilfried2, Author
Chatterjee, Aindrila1, Author
Braun, Laura J.2, Author
Thevenon, Julien2, Author
Sartelet, Herve2, Author
Blank, Thomas2, Author
Grün, Dominic1, Author           
von Elverfeldt, Dominik2, AuthorHuber, Tobias B.2, AuthorVestweber, Dietmar2, AuthorAvilov, Sergiy1, Author           Prinz, Marco2, AuthorBüscher, Jörg Martin1, Author           Akhtar, Asifa1, Author            more..
Affiliations:
1Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, ou_2243640              
2External Organizations, ou_persistent22              

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 Abstract: Mutations in chromatin-modifying complexes and metabolic enzymes commonly underlie complex human developmental syn-dromes affecting multiple organs. A major challenge is to determine how disease-causing genetic lesions cause deregulation of homeostasis in unique cell types. Here we show that neural-specific depletion of three members of the non-specific lethal (NSL) chromatin complex—Mof, Kansl2 or Kansl3—unexpectedly leads to severe vascular defects and brain haemorrhaging. Deregulation of the epigenetic landscape induced by the loss of the NSL complex in neural cells causes widespread metabolic defects, including an accumulation of free long-chain fatty acids (LCFAs). Free LCFAs induce a Toll-like receptor 4 (TLR4)–NFκB-dependent pro-inflammatory signalling cascade in neighbouring vascular pericytes that is rescued by TLR4 inhibition. Pericytes display functional changes in response to LCFA-induced activation that result in vascular breakdown. Our work estab-lishes that neurovascular function is determined by the neural metabolic environment.

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Language(s): eng - English
 Dates: 2020-06-15
 Publication Status: Published online
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 Rev. Type: Peer
 Identifiers: DOI: org/10.1038/s41556-020-0526-8
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Title: Nature Cell Biology
  Other : 'Nat. Cell Biol.'
Source Genre: Journal
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Publ. Info: London : Springer Nature
Pages: - Volume / Issue: 22 Sequence Number: - Start / End Page: 828 - 841 Identifier: ISSN: 1465-7392
CoNE: https://pure.mpg.de/cone/journals/resource/954925625310