DNA double-strand breaks: a potential therapeutic target for neurodegenerative diseases

Abstract

The complexity of neurodegeneration restricts the ability to understand and treat the neurological disorders affecting millions of people worldwide. Therefore, there is an unmet need to develop new and more effective therapeutic strategies to combat these devastating conditions and that will only be achieved with a better understanding of the biological mechanism associated with disease conditions. Recent studies highlight the role of DNA damage, particularly, DNA double-strand breaks (DSBs), in the progression of neuronal loss in a broad spectrum of human neurodegenerative diseases. This is not unexpected because neurons are prone to DNA damage due to their non-proliferative nature and high metabolic activity. However, it is not clear if DSBs is a primary driver of neuronal loss in disease conditions or simply occurs concomitant with disease progression. Here, we provide evidence that supports a critical role of DSBs in the pathogenesis of the neurodegenerative diseases. Among different kinds of DNA damages, DSBs are the most harmful and perilous type of DNA damage and can lead to cell death if left unrepaired or repaired with error. In this review, we explore the current state of knowledge regarding the role of DSBs repair mechanisms in preserving neuronal function and survival and describe how DSBs could drive the molecular mechanisms resulting in neuronal death in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. We also discuss the potential implications of DSBs as a novel therapeutic target and prognostic marker in patients with neurodegenerative conditions.

Keywords: Alzheimer’s disease; DNA damage; DNA repair; Genomic instability, Neurodegeneration; Parkinson’s disease.

Fig. 1

Schematic representation of non-homologous end joining. DNA double-strand break (DSBs) formation is detected by the Ku70/80–DNA-PKcs (DNA-dependent protein kinase). The ends are processed by MRN complex (MRE11, meiotic recombination11; NBS1, Nijmegen breakage syndrome 1). The gaps are filled by polymerase μ and λ and ligated by DNA ligase IV (LIG4). Artemis, X-ray cross-complementing protein 4 (XRCC4), and XRCC4-like factor (XLF; also called Cernunnos) playing a prime role in recruiting LIG4 to carry out the DSBs-joining reaction.

Fig. 2

Schematic representation of homologous recombination. HR involves repair of DSBs in the S and G2 phases using the genetic information coded in the sister chromatid. DSBs are recognized by MRE11-RAD50-NBS1 (MRN) complex and CtIP/MRN initiates DSBs resection, enabling 5′−3′ resection by Exo1/Sgs1 (EXO1/BLM/WRN/DNA2). RAD51 facilitates invasion of the single-stranded 3′-tail into the homologous sister chromatid and forms D-loop; this ensure the highly specific error-free repair of damaged DNA

Fig. 3

Schematic representation of alternative/microhomology-mediated end joining. Alternative/microhomology-mediated end joining acts as a back up pathway for DSBs repair, by annealing 2–20-bp stretches of overlapping bases flanking the DSBs (all alternative pathways does not require microhomology). MRE11-RAD50-XRS2? complex [MRN complex; MRE11-RAD50-XRS2], CtBP-interacting protein (CtIP), and poly(ADP-ribose) polymerase 1 (PARP1) resect the DNA ends and gaps are filled by DNA polymerase theta (Polθ), ligated by Lig3, and mediated by XRCC1

Fig. 4

Proposed mechanisms for the involvement of DNA double-strand breaks in onset and progression of neurodegenerative diseases. DNA double-strand breaks signaling pathways are intertwined through a variety of mechanisms including, ATM activation, ROS generation, and NF-κB activation. The elevated levels of DSBs induce a reduction in the levels of DSBs repair proteins such as DNA-PKcs/Ku70/80 complex and MRN complex proteins, and contributes to progression of AD. ATM/ATR operates through different pathways by p53, BRCA1 proteins, and dopaminergic degeneration. BRCA1 interacts with BRCA2, retinoblastoma protein (Rb), RAD50, RAD51. BRCA1 stimulates the CDK inhibitor p21 WAF1 and p53 tumor suppressor protein. DSBs directly activate NF-κB in a membrane receptor-independent manner or activated through ATM. NF-κB upregulation triggers NLRP3 activation and secretion of proinflammatory cytokines in Alzheimer disease and Parkinson’s disease.