FUS May Help Keep Motor Neurons’ Genomes In Good Nick

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.

In Bad Nick? In FUS ALS, DNA damage due to oxidative stress may be unable to be repaired, contributing to neurotoxicity. [Courtesy of Wang et al., 2018, Nature Communications. CC BY 4.0].

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.

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To learn more about the emerging role of DNA damage in ALS, check out Targeting FUS: DNA Damage Control in ALS.

Featured Paper

Wang H, Guo W, Mitra J, Hegde PM, Vandoorne T, Eckelmann BJ, Mitra S, Tomkinson AE, Van Den Bosch L, Hegde ML. Mutant FUS causes DNA ligation defects to inhibit oxidative damage repair in Amyotrophic Lateral Sclerosis. Nat Commun. 2018 Sep 11;9(1):3683. PubMed.

References

Naumann M, Pal A, Goswami A, Lojewski X, Japtok J, Vehlow A, Naujock M, Günther R, Jin M, Stanslowsky N, Reinhardt P, Sterneckert J, Frickenhaus M, Pan-Montojo F, Storkebaum E, Poser I, Freischmidt A, Weishaupt JH, Holzmann K, Troost D, Ludolph AC, Boeckers TM, Liebau S, Petri S, Cordes N, Hyman AA, Wegner F, Grill SW, Weis J, Storch A, Hermann A. Impaired DNA damage response signaling by FUS-NLS mutations leads to neurodegeneration and FUS aggregate formation. Nat Commun. 2018 Jan 23;9(1):335. PubMed.

Wang WY, Pan L, Su SC, Quinn EJ, Sasaki M, Jimenez JC, Mackenzie IR, Huang EJ, Tsai LH. Interaction of FUS and HDAC1 regulates DNA damage response and repair in neurons. Nat Neurosci. 2013 Oct;16(10):1383-91. PubMed.

Rulten SL, Rotheray A, Green RL, Grundy GJ, Moore DA, Gómez-Herreros F, Hafezparast M, Caldecott KW. PARP-1 dependent recruitment of the amyotrophic lateral sclerosis-associated protein FUS/TLS to sites of oxidative DNA damage. Nucleic Acids Res. 2014 Jan;42(1):307-14.  PubMed.

Further Reading

Walker C, Herranz-Martin S, Karyka E, Liao C, Lewis K, Elsayed W, Lukashchuk V, Chiang SC, Ray S, Mulcahy PJ, Jurga M, Tsagakis I, Iannitti T, Chandran J, Coldicott I, De Vos KJ, Hassan MK, Higginbottom A, Shaw PJ, Hautbergue GM, Azzouz M, El-Khamisy SF. C9orf72 expansion disrupts ATM-mediated chromosomal break repair. Nat Neurosci. 2017 Sep;20(9):1225-1235. PubMed.

Higelin J, Catanese A, Semelink-Sedlacek LL, Oeztuerk S, Lutz AK, Bausinger J, Barbi G, Speit G, Andersen PM, Ludolph AC, Demestre M, Boeckers TM. NEK1 loss-of-function mutation induces DNA damage accumulation in ALS patient-derived motoneurons. Stem Cell Res. 2018 Jul;30:150-162. PubMed.

Coppedè F, Migliore L. DNA damage in neurodegenerative diseases. Mutat Res. 2015 Jun;776:84-97. PubMed.

 

 

disease-als DNA damage DNA damage response DNA repair FUS oxidative stress single-stranded breaks SSBs topic-preclinical
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