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

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

Nature cell biology (2020-06-17)
Bilal N Sheikh, Sukanya Guhathakurta, Tsz Hong Tsang, Marius Schwabenland, Gina Renschler, Benjamin Herquel, Vivek Bhardwaj, Herbert Holz, Thomas Stehle, Olga Bondareva, Nadim Aizarani, Omar Mossad, Oliver Kretz, Wilfried Reichardt, Aindrila Chatterjee, Laura J Braun, Julien Thevenon, Herve Sartelet, Thomas Blank, Dominic Grün, Dominik von Elverfeldt, Tobias B Huber, Dietmar Vestweber, Sergiy Avilov, Marco Prinz, Joerg M Buescher, Asifa Akhtar
ABSTRACT

Mutations in chromatin-modifying complexes and metabolic enzymes commonly underlie complex human developmental syndromes 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 establishes that neurovascular function is determined by the neural metabolic environment.

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