HAT cofactor TRRAP modulates microtubule dynamics via SP1 signaling to prevent neurodegeneration
Autor: | Alicia Tapias, David Lázaro, Bo-Kun Yin, Seyed Mohammad Mahdi Rasa, Anna Krepelova, Erika Kelmer Sacramento, Paulius Grigaravicius, Philipp Koch, Joanna Kirkpatrick, Alessandro Ori, Francesco Neri, Zhao-Qi Wang |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
Aging
Mouse QH301-705.5 Science cell lines Microtubule dynamics SP1 transcription factor Microtubules Epigenesis Genetic Mice Purkinje Cells stathmins Animals Biology (General) Neurodegeneration Adaptor Proteins Signal Transducing Brain Nuclear Proteins Chromosomes and Gene Expression Mice Mutant Strains TRRAP SP1 Gene Expression Regulation Neuroscience HAT Medicine Gene Deletion Research Article Signal Transduction |
Zdroj: | eLife, 10:e61531 eLife eLife, Vol 10 (2021) |
Popis: | 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. |
Databáze: | OpenAIRE |
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