To live or to die: a matter of processing damaged DNA termini in neurons

Abstract

Defects in the repair of deoxyribonucleic acid (DNA) damage underpin several hereditary neurological diseases in humans. Of the different activities that repair chromosomal DNA breaks, defects in resolving damaged DNA termini are among the most common causes of neuronal cell death. Here, the molecular mechanisms of some of the DNA end processing activities are reviewed and the association with human neurodegenerative disease is discussed.

Figure 1. The cerebellum is a common target for disorders with DNA repair defects

Ataxia telagiectasia (AT), Spinocerebellar ataxia with axonal neuropathy 1 (SCAN1), Ataxia oculomotor apraxia 1 (AOA1), and Ataxia ocuolomotor apraxia 2 (AOA2) are DNA repair-related disorders that share cerebellar degeneration as the most striking clinical feature. In contrast to AT where patients present with immunodeficiency and cancer, symptoms of SCAN1, AOA1 and AOA2 appear to be restricted to the nervous system. It is interesting to note that there is some degree of overlap in the extra-neurological features. Whereas AT and AOA2 patients present with high levels of AFP, SCAN1 and AOA1 present with reduced levels of serum albumin. This may reflect a consequence of the associated DNA repair defect or arise as a result of progressive functional decline.

Figure 2. Repair of topoisomerase-mediated DNA damage and neurodegeneration: same pathway with different clinical features

Stalled DNA topoisomerase 1 (Top1) is subjected to proteasomal degradation to form a smaller peptide that is then acted upon by TDP1. TDP1 cleaves the phosphodiester bond between Top1 peptide and DNA, creating 3′-phosphate and 5′-hydroxyl termini. In preparation for ligation, PNKP restores conventional 3′-hydroxyl and 5′-phosphate termini, followed by sealing the nick by a DNA ligase. Mutations in CUL4B (involved in proteasomal degradation) underlie defects in the degradation step of DNA topoisomerase 1 repair, causing mental retardation and motor neuron impairment in XLMR. Defects in the downstream step catalysed by TDP1 causes cerebellar degeneration and peripheral neuropathy typified by patients with SCAN1. Mutations in PNKP underlie microcephaly and seizures observed in MCSZ.

Figure 3. The mitochondrial dysfunction, DNA damage, and aging triangle

Accumulation of mutations with age has been extensively studied in mice and humans as one cause of ‘physiological’ aging. DNA damage can also cause downregulation of genes that are normally associated with the extension of life span, such as IGF-1 and GH, contributing to the aging process. On the other hand, aging leads to reduced expression of DNA repair factors, leading to increased accumulation of DNA damage. Aging also may cause reduced trafficking of DNA repair factors to the mitochondria, contributing to mitochondrial dysfunction. The latter results in defects in the oxidative phosphorylation leading to increased production of ROS and consequent accumulation of DNA damage in mtDNA. This vicious cycle can potentially be broken by counteracting any of its components. For example, enhancing DNA repair by the use of small molecule based approaches or gene therapy may reduce the extent of DNA damage. Anti-oxidants and caloric restriction may reduce the extent of mitochondrial dysfunction and delay the symptoms of aging.