Histone H3 Ser57 and Thr58 Phosphorylation in 5XFAD Mouse Brain
Kyle W. Anderson, Illarion V. Turko, Natalia Mast, Irina A. Pikuleva
Alzheimers disease (AD) is the most common neurodegenerative disorder, yet it is poorly understood. Currently, there is no treatment to delay onset or slow progression of AD. Epigenetics of AD is a growing field that has gained interest due to the repression of gene transcription that is consistently observed in neurodegeneration. Among the changes associated with gene expression and chromatin remodeling are post-translational modifications (PTMs) of histones. Most investigation is limited to the N-terminus, or tail region, of histones and little research has been conducted on PTMs in the core region. Phosphorylation is a common PTM that is associated with repressed or active genes depending on the site of phosphorylation. Histone H3 has been shown to be highly regulated by phosphorylation. We, therefore, chose H3 for investigation of phosphorylation of the core sites serine-57 (S57) and threonine-58 (T58). Whole hemispheres of brains from mouse models of rapid amyloid deposition (5XFAD) were used for measurement of S57 and T58 phosphorylation. Multiple reaction monitoring (MRM) was used to measure level of phosphorylation, which was normalized to a non-modified housekeeping peptide of H3. S57 phosphorylation decreased 40 %, T58 phosphorylation decreased 45 %, and doubly phosphorylated S57pT58p decreased 30 % in 5XFAD brain in comparison to B6SJLF1/J age- and sex-matched wild type controls. Decreased phosphorylation of these sites in close proximity to DNA may lead to stabilization of DNA-histone interactions and a condensed chromatin state, consistent with the epigenetic blockade associated with AD. Efavirenz (EFV), a reverse transcriptase inhibitor for HIV treatment, is suggested to have neuroprotective affects at low dose concentrations. To evaluate the effect of EFV on S57 and T58 phosphorylation, we treated 5XFAD mice with EFV for 3 months. However, no statistically significant changes in phosphorylation after EFV treatment were observed.
, Turko, I.
, Mast, N.
and Pikuleva, I.
Histone H3 Ser57 and Thr58 Phosphorylation in 5XFAD Mouse Brain, FEBS Open Bio, [online], https://doi.org/10.1016/j.fob.2015.06.009
(Accessed November 28, 2023)