Quantification of histone deacetylase isoforms in human frontal cortex, human retina, and mouse brain.

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TitleQuantification of histone deacetylase isoforms in human frontal cortex, human retina, and mouse brain.
Publication TypeJournal Article
Year of Publication2015
AuthorsAnderson, KW, Chen, J, Wang, M, Mast, N, Pikuleva, IA, Turko, IV
JournalPLoS One
Volume10
Issue5
Paginatione0126592
Date Published2015
ISSN1932-6203
KeywordsAnimals, Brain, Chromatography, Liquid, Female, Frontal Lobe, Histone Deacetylases, Humans, Isoenzymes, Male, Mice, Retina, Tandem Mass Spectrometry
Abstract

Histone deacetylase (HDAC) inhibition has promise as a therapy for Alzheimer's disease (AD) and other neurodegenerative diseases. Currently, therapeutic HDAC inhibitors target many HDAC isoforms, a particularly detrimental approach when HDAC isoforms are known to have different and specialized functions. We have developed a multiple reaction monitoring (MRM) mass spectrometry assay using stable isotope-labeled QconCATs as internal standards to quantify HDAC isoforms. We further determined a quantitative pattern of specific HDACs expressed in various human and mouse neural tissues. In human AD frontal cortex, HDAC1,2 decreased 32%, HDAC5 increased 47%, and HDAC6 increased 31% in comparison to age-matched controls. Human neural retina concentrations of HDAC1, 2, HDAC5, HDAC6, and HDAC7 decreased in age-related macular degeneration (AMD)-affected donors and exhibited a greater decrease in AD-affected donors in comparison to age-matched control neural retinas. Additionally, HDAC concentrations were measured in whole hemisphere of brain of 5XFAD mice, a model of β-amyloid deposition, to assess similarity to AD in human frontal cortex. HDAC profiles of human frontal cortex and mouse hemisphere had noticeable differences and relatively high concentrations of HDAC3 and HDAC4 in mice, which were undetectable in humans. Our method for quantification of HDAC isoforms is a practical and efficient technique to quantify isoforms in various tissues and diseases. Changes in HDAC concentrations reported herein contribute to the understanding of the pathology of neurodegeneration.

DOI10.1371/journal.pone.0126592
Alternate JournalPLoS ONE
PubMed ID25962138
PubMed Central IDPMC4427357
Grant ListP30 EY011373 / EY / NEI NIH HHS / United States
EY018383 / EY / NEI NIH HHS / United States
P50 AG005681 / AG / NIA NIH HHS / United States
R01 GM062882 / GM / NIGMS NIH HHS / United States
EY011373 / EY / NEI NIH HHS / United States
GM062882 / GM / NIGMS NIH HHS / United States
R01 EY018383 / EY / NEI NIH HHS / United States