Histone Post-Translational Modifications and DNA Double-Strand Break Repair in Neurodegenerative Diseases: An Epigenetic Perspective

TL;DR

This paper explores how changes in histone modifications affect DNA repair in neurons, contributing to neurodegenerative diseases.

Contribution

The paper reviews how histone post-translational modifications influence DNA repair in neurodegenerative diseases, highlighting novel therapeutic targets.

Findings

Histone PTMs play a crucial role in DNA double-strand break repair in neurons.

Altered histone PTM levels are linked to DNA repair defects in diseases like Alzheimer's and Parkinson's.

Targeting histone PTMs could offer new strategies to prevent neurodegeneration.

Abstract

Neurodegeneration is a fatal process often involving damage to the genome. The post-mitotic status of neurons make DNA repair an essential and crucial process to prevent neurodegeneration. Histone post-translational modification is an epigenetic mechanism that aids in DNA repair, dysregulation of which can contribute to persistent DNA damage followed by neuronal death. This review summarizes histone post-translational modifications involved specifically in DNA double-strand break repair and alterations in the level of certain DNA repair-related histone marks in various neurodegenerative diseases. Further evaluation of histone modifications associated with DNA repair in relevant disease models would provide mechanistic insights into neurodegeneration, as well as reveal novel targets and preventative strategies.

DNA damage is a hallmark of the fatal process of neurodegeneration in the central nervous system (CNS). As neurons are terminally differentiated, they accumulate metabolic and oxidative burdens over their whole life span. Unrepaired DNA develops into DNA double-strand breaks (DSBs), which are repaired through homologous recombination (HR) or non-homologous end joining (NHEJ). Being post-mitotic and unable to normally undergo HR, damage and defective repair is especially burdensome to CNS neurons. Current research has not produced treatment to prevent and halt progression of neurodegeneration. Hence, novel targeting strategies are desperately needed. Recent investigations in histone post-translational modifications (PTMs) reveal new mechanistic insight and highlight unexplored targets to ameliorate neurodegeneration. As various histone PTMs dictate and facilitate DSB repair, they represent an underexploited area in investigating DNA damage and incorrect repair aiding neurodegeneration. Here, we review the histone PTM alterations in several neurodegenerative diseases: Amyotrophic Lateral Sclerosis/Frontotemporal Dementia, Parkinson’s Disease, Alzheimer’s Diseases, Multiple Sclerosis, and Huntington’s Disease. These findings emphasize that histone PTM alterations can enable an aberrant DNA damage response (DDR) leading to neurodegeneration. Further research into the connections between histone PTMs and DNA damage in decaying neurons will illuminate novel targets to dampen the aberrant DDR and promote neuronal survival.

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