title: Quantification of histone deacetylase isoforms in human frontal cortex, human retina, and mouse brain.
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.
authors.affiliation: Institute for Bioscience and Biotechnology Research, Rockville, Maryland, United States of America; Biomolecular Measurement Division, National Institute of Standards and Technology, Gaithersburg, Maryland, United States of America; Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland, United States of America.
authors.forename: Kyle W
authors.initials: KW
authors.lastname: Anderson
authors.affiliation: Institute for Bioscience and Biotechnology Research, Rockville, Maryland, United States of America; Biomolecular Measurement Division, National Institute of Standards and Technology, Gaithersburg, Maryland, United States of America.
authors.forename: Junjun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Institute for Bioscience and Biotechnology Research, Rockville, Maryland, United States of America; Biomolecular Measurement Division, National Institute of Standards and Technology, Gaithersburg, Maryland, United States of America.
authors.forename: Meiyao
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Natalia
authors.initials: N
authors.lastname: Mast
authors.affiliation: Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Irina A
authors.initials: IA
authors.lastname: Pikuleva
authors.affiliation: Institute for Bioscience and Biotechnology Research, Rockville, Maryland, United States of America; Biomolecular Measurement Division, National Institute of Standards and Technology, Gaithersburg, Maryland, United States of America.
authors.forename: Illarion V
authors.initials: IV
authors.lastname: Turko
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002853:Chromatography, Liquid; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes; D008297:Male; D051379:Mice; D012160:Retina / Q000378:metabolism*; D053719:Tandem Mass Spectrometry
chemical_list: D007527:Isoenzymes; D006655:Histone Deacetylases