Emerging Perspectives on DNA Double-strand Breaks in Neurodegenerative Diseases

Abstract

DNA double-strand breaks (DSBs) are common events that were recognized as one of the most toxic lesions in eukaryotic cells. DSBs are widely involved in many physiological processes such as V(D)J recombination, meiotic recombination, DNA replication and transcription. Deregulation of DSBs has been reported in multiple diseases in human beings, such as the neurodegenerative diseases, with which the underlying mechanisms are needed to be illustrated. Here, we reviewed the recent insights into the dysfunction of DSB formation and repair, contributing to the pathogenesis of neurodegenerative disorders including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and ataxia telangiectasia (A-T).

Keywords: DNA double-strand breaks; alzheimer’s disease; amyotrophic lateral sclerosis; apoptosis; histone modifications; huntington’s disease; neurodegenerative diseases..

Fig. (1)

Repair of DSBs through HR and NHEJ. (left) MRN activates DNA cutting to generate 3’ ssDNA overhang which is later wrapped by RPA for protection. Then BRCA2 mediates RAD51 to form nucleoprotein filament. Strain is synthesized after invasion of template DNA. (right) DNA-PKcs is recruited to form DNA-PK after Ku70/80 recognizes break sites. DNA-PK arranges broken ends to get close correctly. Artemis nuclease cuts the overhang and hairpin sequences. Then broken ends are connected by XRCC4-XLF-Lig IV. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Fig. (2)

Aβ reduces expression of BRCA1 through extrasynaptic NMDARs activation. Aβ decreases GLAST and GLT-1 expression in astrocytes to reduce uptake of glutamine and induces glutamine spillover to extrasynaptic NMDARs. Activation of extrasynaptic NMDARs leads to decrease of DSB repair factor BRCA1. Then decreased BRCA1 causes long-term synaptic plasticity impairment as well as learning and memory deficiency. (A higher resolution / colour version of this figure is available in the electronic copy of the article).