Epigenetics of Neurodegeneration: Quantification of Histone Deacetylase Isoforms and Post-translational Modifications of Histones in Alzheimer’s Disease

Abstract

Histone post-translational modifications have been implicated in many biological functions and diseases and serve an important role in epigenetic regulation of gene expression. Aberrant modulations in histone post-translational have been suggested to occur in the brain as part of Alzheimer’s disease (AD) pathology, consistent with the epigenetic blockade of neurodegeneration. This dissertation details the development and optimization of unique protein standards for quantification, called quantification concatamers, for the absolute quantification of histone deacetylase isoforms in human frontal cortex with AD, human neural retina with AD and age-related macular degeneration, and whole brain hemisphere of a 5XFAD mouse model of AD. Histone deacetylases are enzymes responsible for the deacetylation of histones, which can directly regulate transcription, and have been implicated in AD pathology. In addition to measuring isoforms of histone-modifying enzymes, measurements of post-translational modifications on histones were also obtained for whole hemispheres of brain from 5XFAD mice and frontal cortex from human donors affected with AD. For the changes in post-translational modifications observed, structural mechanisms were proposed to explain alterations in the DNA-histone affinity in the nucleosome, which can modulate gene expression. Measurements and structural mechanisms were consistent with the global decrease in gene expression observed in AD, which supports the data. This body of work aims to better elucidate the epigenetic pathology of AD and to aid in identification of histone-modifying enzymes involved in AD pathology for drug targets and treatment options. Currently, there are no treatments that prevent, delay, or ameliorate AD, stressing the crucial importance of AD pathology research and the promise of epigenetics as the solution.