Modulating Cognition-Linked Histone Acetyltransferases (HATs) as a Therapeutic Strategy for Neurodegenerative Diseases: Recent Advances and Future Trends

Abstract

Recent investigations into the neuroepigenome of the brain are providing unparalleled understanding into the impact of post-translational modifications (PTMs) of histones in regulating dynamic gene expression patterns required for adult brain cognitive function and plasticity. Histone acetylation is one of the most well-characterized PTMs shown to be required for neuronal function and cognition. Histone acetylation initiates neural circuitry plasticity via chromatin control, enabling neurons to respond to external environmental stimuli and adapt their transcriptional responses accordingly. While interplay between histone acetylation and deacetylation is critical for these functions, dysregulation during the aging process can lead to significant alterations in the neuroepigenetic landscape. These alterations contribute to impaired cognitive functions, neuronal cell death, and brain atrophy, all hallmarks of age-related neurodegenerative disease. Significantly, while age-related generation of DNA mutations remains irreversible, most neuroepigenetic PTMs are reversible. Thus, manipulation of the neural epigenome is proving to be an effective therapeutic strategy for neuroprotection in multiple types of age-related neurodegenerative disorders (NDs) that include Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). Here, we highlight recent progress in research focusing on specific HAT-based neuroepigenetic mechanisms that underlie cognition and pathogenesis that is hallmarked in age-related NDs. We further discuss how these findings have potential to be translated into HAT-mediated cognitive-enhancing therapeutics to treat these debilitating disorders.

Keywords: cell death; histone acetyltransferases (HATs); histone code; histone deacetylases (HDACs); learning and memory; neurodegenerative diseases (NDs); neuroepigenetics; synaptic plasticity.

Figure 1

HAT families in brain function and cognition. The three most notable HAT families that are required for brain function and cognition are the CBP/p300, MYST, and GNAT. Their functional roles in the specific cognition-linked neuronal cellular processes they control are illustrated.

Figure 2

HAT-mediated neuroepigenetic alterations drive multiple age-related neurodegenerative diseases. Reduced HAT and histone acetylation levels are found in the brains of animal models for multiple types of neurodegenerative diseases. Pharmacological treatments aimed at increasing histone acetylation by inhibiting HDAC action or activating specific HATs in these models have shown reversal of cognitive deficits and are thus a topic of intense research. This schematic provides an overview of data linking impaired control of specific HATs and HDACs to alterations in the neuroepigenome that contribute to multiple neurodegenerative diseases.