An overview of DNA repair in amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is an adult onset neurodegenerative disorder characterised by the degeneration of cortical and spinal cord motor neurons, resulting in progressive muscular weakness and death. Increasing evidence supports mitochondrial dysfunction and oxidative DNA damage in ALS motor neurons. Several DNA repair enzymes are activated following DNA damage to restore genome integrity, and impairments in DNA repair capabilities could contribute to motor neuron degeneration. After a brief description of the evidence of DNA damage in ALS, this paper focuses on the available data on DNA repair activity in ALS neuronal tissue and disease animal models. Moreover, biochemical and genetic data on DNA repair in ALS are discussed in light of similar findings in other neurodegenerative diseases.

Keywords: Amyotrophic lateral sclerosis; DNA damage; DNA repair; base excision repair; neurodegeneration.

Figure 1

Diagram illustrating the DNA base excision repair (BER) pathway. In this pathway, a DNA glycosylase catalyzes the removal of a damaged base, creating an abasic (AP) site. The APEX1 endonuclease catalyzes the incision of the DNA backbone leaving behind a 5′-deoxyribose phosphate (5′dRP, indicated with a black circle). In short-patch BER, polymerase β (Pol β) displaces the AP site and polymerizes DNA to fill in the gap. Pol β then catalyzes the removal of the displaced AP site, and the ligase III/XRCC1 complex seals the ends. If the 5′dRP is refractory to the action of Pol β, then an additional synthesis of DNA (long-patch BER) is required to displace the modified 5′-sugar phosphate as part of a flap (in grey), which is then removed by flap endonuclease (FEN1). Pol β adds the first nucleotide into the gap and is substituted by polymerase δ/ε which continues long-patch BER. DNA ligase I (LIG1) completes the long-patch pathway.