Quantification of Histone Deacetylase Isoforms in Human Frontal Cortex, Human Retina, and Mouse Brain
Kyle W. Anderson, Illarion V. Turko, Meiyao M. Wang, Junjun J. Chen, Irina A. Pikuleva, Natalia Mast
Histone deacetylases (HDACs) are primarily responsible for the deacetylation of histones, thereby regulating gene expression, as well as modifying many non-histone proteins. HDAC inhibition has promise as a therapy for Alzheimers disease (AD) and other neurodegenerative diseases based on research in animal models. Currently, therapeutic HDAC inhibition in animal models uses pan-inhibitors, targeting many HDAC isoforms, a particularly detrimental approach when HDAC isoforms are known to have different, specialized functions in the brain. To quantify HDAC isoforms in biological samples, we employed multiple reaction monitoring (MRM) mass spectrometry using QconCATs as stable-isotope, multiplexing standards. We determined concentrations of specific HDAC isoforms in frontal cortex of AD-affected human donors and age-matched controls as well as in human neural retina of non-AD and AD-affected donors and those with age-related macular degeneration (AMD). Additionally, HDAC concentrations were measured in the brain of wild type and 5XFAD mice, a model of β-amyloid deposition in AD, and compared to those in human frontal cortex of AD-affected and normal donors. Human and mouse cerebral HDAC profiles had noticeable differences in control and disease-affected samples with relatively high concentrations of HDAC3 and HDAC4 in mice, which were undetectable in humans. Moreover, our proof-of-concept study demonstrates MRM quantification of HDAC isoforms by QconCATs can be applied to various tissues and diseases. With growing interest in specific HDAC isoform inhibition for improved efficacy and safety in many diseases, our method can be a useful tool in pathology research.
, Turko, I.
, Wang, M.
, Chen, J.
, Pikuleva, I.
and Mast, N.
Quantification of Histone Deacetylase Isoforms in Human Frontal Cortex, Human Retina, and Mouse Brain, PLoS One, [online], https://doi.org/10.1371/journal.pone.0126592
(Accessed November 29, 2023)