HAT cofactor TRRAP modulates microtubule dynamics via SP1 signaling to prevent neurodegeneration.

Autor:	Tapias A; Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany., Lázaro D; Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany., Yin BK; Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany., Rasa SMM; Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany., Krepelova A; Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany., Kelmer Sacramento E; Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany., Grigaravicius P; Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany., Koch P; Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany., Kirkpatrick J; Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany., Ori A; Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany., Neri F; Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany., Wang ZQ; Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany.; Faculty of Biological Sciences, Friedrich-Schiller-University of Jena, Jena, Germany.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2021 Feb 17; Vol. 10. Date of Electronic Publication: 2021 Feb 17.
DOI:	10.7554/eLife.61531
Abstrakt:	Brain homeostasis is regulated by the viability and functionality of neurons. HAT (histone acetyltransferase) and HDAC (histone deacetylase) inhibitors have been applied to treat neurological deficits in humans; yet, the epigenetic regulation in neurodegeneration remains elusive. Mutations of HAT cofactor TRRAP (transformation/transcription domain-associated protein) cause human neuropathies, including psychosis, intellectual disability, autism, and epilepsy, with unknown mechanism. Here we show that Trrap deletion in Purkinje neurons results in neurodegeneration of old mice. Integrated transcriptomics, epigenomics, and proteomics reveal that TRRAP via SP1 conducts a conserved transcriptomic program. TRRAP is required for SP1 binding at the promoter proximity of target genes, especially microtubule dynamics. The ectopic expression of Stathmin3/4 ameliorates defects of TRRAP-deficient neurons, indicating that the microtubule dynamics is particularly vulnerable to the action of SP1 activity. This study unravels a network linking three well-known, but up-to-date unconnected, signaling pathways, namely TRRAP, HAT, and SP1 with microtubule dynamics, in neuroprotection. Competing Interests: AT, DL, BY, SR, AK, EK, PG, PK, JK, AO, FN, ZW No competing interests declared (© 2021, Tapias et al.)
Databáze:	MEDLINE
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