DNA damage may occur early in at least some forms of ALS, contributing to motor neuron toxicity (see March 2018 news). But why this damage may go unrepaired remains unclear.
A growing number of ALS-linked proteins such as FUS help fix the genome, suggesting that targeting the DNA damage response may be of benefit in the disease (see September 2013 news).
Now, a research team led by Houston Methodist Hospital’s Muralidhar Hegde in Texas reports that FUS helps repair DNA damaged due to oxidative stress, including single-stranded breaks, by recruiting and activating DNA ligase IIIα-XRCC1. What’s more, increased levels of these breaks could be detected in patient-derived FUS ALS motor neurons.
The findings build on previous studies led by University of Sussex’s Keith Caldecott in England, which found that FUS is recruited to sites of oxidative damage in the genome by a PARP-1 dependent mechanism (Rulten et al., 2014).
Together, the results suggest that FUS may play a key role in fixing DNA damage in motor neurons due to oxidative stress. Increased levels of reactive oxygen species are thought to be a key source of neurotoxicity in ALS (see February 2013 news; July 2017 news; for review, see Coppedè and Migliore, 2015).
The study appeared on September 11 in Nature Communications.
FUS is thought to play a key role in maintaining the structural integrity of the genome, particularly by mediating the repair of double-stranded DNA breaks (see September 2013 news; Wang et al., 2013). The accumulation of double-stranded breaks may contribute to ALS by promoting the mislocalization of FUS, leading to a “vicious cycle” of motor neuron toxicity (see March 2018 news; Naumann et al., 2018).
Efforts to target the DNA damage response in ALS are currently ongoing (see March 2018 news). Stay tuned.
To learn more about the emerging role of DNA damage in ALS, check out Targeting FUS: DNA Damage Control in ALS.
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