Age-Related DNA Damage
The mammalian genome is under constant attack from both endogenous and exogenous sources. This can result in DNA damage, mutations and impaired cellular viability if not repaired correctly (Madabhushi et al., 2014). There is a significant increase in DNA damage during aging due to reduced capacity of DNA repair. Moreover, erroneous repair of DNA lesions can result in further mutations in the aged brain (Vijg and Suh, 2013). DNA damage is increasingly implicated in neurodegenerative disorders, including ALS, where it is induced by the C9orf72 repeat expansion (Farg et al., 2017; Walker et al., 2017). Interestingly, there is also evidence that both FUS and TDP-43 function in the DNA damage response, in either prevention of damage or repair of R loop-associated DNA damage (Hill et al., 2016). In addition, impairment of the DNA damage response due to the presence of ALS/FTD-associated FUS mutations induces neurodegeneration (Higelin et al., 2016; Naumann et al., 2018). It is therefore possible that the normal aging process results in an impaired ability to repair DNA in MNs. This may be an important source of cellular stress that precipitates neurodegeneration in cells already exposed to pathological events throughout life. However, recent work suggests that mutant SOD1G93A does not impact on DNA strand integrity, implying that DNA damage is not present in all forms of ALS (Penndorf et al., 2017).