HAT cofactor TRRAP modulates microtubule dynamics via SP1 signaling to prevent neurodegeneration
Authors: Joanna Kirkpatrick
Alicia Tapias
Francesco Neri
Bo-Kun Yin
Alessandro Ori
Philipp Koch
Anna Krepelova
Seyed Mohammad Mahdi Rasa
Zhao-Qi Wang
Paulius Grigaravicius
Erika Kelmer Sacramento
David Lázaro
Journal: eLife (2021)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Brain; SP1; TRRAP; cell lines; chromosomes
Affiliations: Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany., Faculty of Biological Sciences, Friedrich-Schiller-University of Jena, Jena, Germany.

Abstract:  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. 

Retracted: No

PubPeer comments:
 In Fig. 1A, a repeated-measures rather than a two-way ANOVA should have been used, and the requirement for equal variances seems to have been violated. However, I don t believe the basic result will be altered with a correct analysis. In Fig. 1CE, the authors have a two-factor design (age, genotype) and should be exploring the interaction term in a two-way ANOVA. Instead they perform a one-way ANOVA. Moreover, the groups clearly have very unequal variances in some cases. I wouldn t expect the results of the rightmost panel to survive in a corrected analysis. In Fig. 2CEFG the authors should also be using a two-way ANOVA and looking at the interaction term. Furthermore, in panels CEF cellular measurements are nested within animals. Although the authors give the numbers of animals (except in C) and the numbers of measurements, they do not give the degrees of freedom used in the tests. It is, however, likely to have been based on the total number of measurements rather than the numbers of animals. In other words, CEF display pseudoreplication. In Fig. 3F, I believe a two-way ANOVA should have been used and the interaction term examined. The legend states an unparied t-test was used. Does the difference between controls survive a Welch test, which should be used because of the very obviously different variances? Is the data available if one wishes to redo this calculation? In Fig. BC, we encounter again the issue of a nested design (cells within animals) and without information about the degrees of freedom it is hard to know whether the authors are practising pseudoreplication. I also found it hard to understand the following phrase  Each bar represents the data from four to six mouse embryos; the experiments were repeated more than three times. What exactly was repeated three times at least? ,