DNA Damage-Induced Neurodegeneration in Accelerated Ageing and Alzheimer's Disease

Abstract

DNA repair ensures genomic stability to achieve healthy ageing, including cognitive maintenance. Mutations on genes encoding key DNA repair proteins can lead to diseases with accelerated ageing phenotypes. Some of these diseases are xeroderma pigmentosum group A (XPA, caused by mutation of XPA), Cockayne syndrome group A and group B (CSA, CSB, and are caused by mutations of CSA and CSB, respectively), ataxia-telangiectasia (A-T, caused by mutation of ATM), and Werner syndrome (WS, with most cases caused by mutations in WRN). Except for WS, a common trait of the aforementioned progerias is neurodegeneration. Evidence from studies using animal models and patient tissues suggests that the associated DNA repair deficiencies lead to depletion of cellular nicotinamide adenine dinucleotide (NAD⁺), resulting in impaired mitophagy, accumulation of damaged mitochondria, metabolic derailment, energy deprivation, and finally leading to neuronal dysfunction and loss. Intriguingly, these features are also observed in Alzheimer's disease (AD), the most common type of dementia affecting more than 50 million individuals worldwide. Further studies on the mechanisms of the DNA repair deficient premature ageing diseases will help to unveil the mystery of ageing and may provide novel therapeutic strategies for AD.

Keywords: Alzheimer’s disease (AD); DNA damage; DNA repair; age-related disease.

Figure 1

Schematic of BER in mammalian cells. BER is the key pathway to remove and repair damaged bases. It starts with a DNA glycosylase to recognize and eliminate the damaged base, creating an abasic site. The gap is finally filled by DNA polymerases. The short patch is repaired with a single nucleotide, and the long patch is synthesized with 2–13 nucleotides.

Figure 2

Schematic of NER and DSBR in mammalian cells. (a) NER is composed of GG-NER and TC-NER. XPC scans the double helix to identify the lesion, and forms a complex with centrins, HR23B among others, to induce NER activity. Subsequently XPA and TFIIH act as translocase and helicase to unwind the DNA. The DNA lesion is excised by XPF and XPG. Finally, the gap is filled by DNA polymerases and DNA ligase I. (b) DSBR consists HR and NHEJ. HR is initiated by MRN. Rad51 participates in the search for homologous copies, and its homologues are involved in DNA strand invasion and subsequent homologous recombination to repair. NHEJ is activated by Ku80/Ku70. The damaged ends are trimmed by artemis; after that, the gap is filled by the action of DNA polymerase. The final repair is mediated by DNA ligase IV and cofactor XRCC4.

Figure 3

Schematic of the availability of different DNA repair pathways during different stages of neuronal development.

Figure 4

Crosstalk between nucleus and mitochondria in premature ageing and AD. Nuclear DNA damage can lead to mitochondrial dysfunction. One of the pathways through which the nucleus regulates mitochondrial function is the PARP1–NAD⁺–SIRT1 signaling pathway. NAD⁺ plays an important role as a reaction substrate in various pathways of DDR. Together, these contribute to ageing and the neurodegeneration in accelerated ageing. Black arrows indicate promotion, and inverted T bars indicate repression. Red arrows indicate up- or downregulation.