Journal
CELLULAR AND MOLECULAR LIFE SCIENCES
Volume 78, Issue 15, Pages 5707-5729Publisher
SPRINGER BASEL AG
DOI: 10.1007/s00018-021-03872-0
Keywords
Amyotrophic lateral sclerosis; Neurodegeneration; DNA damage; DNA damage response; Astrocytes
Categories
Funding
- MRC Discovery Medicine North (DiMeN) Doctoral Training Partnership [MR/R015902/1]
- AstraZeneca
- Academy of Medical Sciences [SBF002\1142]
- UKRI [MR/W00416X/1]
- Wellcome Trust [103844]
- Lister Institute of Preventative Medicine [137661]
Ask authors/readers for more resources
Increasing evidence supports the involvement of DNA damage in various neurodegenerative diseases, including ALS. DNA damage in ALS may vary between genetic subgroups, particularly with repeat expansion in the C9ORF72 gene. Several genes associated with ALS, such as TARDBP, FUS, NEK1, SQSTM1 and SETX, may contribute to neuronal death by affecting DNA repair and the DNA damage response.
Increasing evidence supports the involvement of DNA damage in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Elevated levels of DNA damage are consistently observed in both sporadic and familial forms of ALS and may also play a role in Western Pacific ALS, which is thought to have an environmental cause. The cause of DNA damage in ALS remains unclear but likely differs between genetic subgroups. Repeat expansion in the C9ORF72 gene is the most common genetic cause of familial ALS and responsible for about 10% of sporadic cases. These genetic mutations are known to cause R-loops, thus increasing genomic instability and DNA damage, and generate dipeptide repeat proteins, which have been shown to lead to DNA damage and impairment of the DNA damage response. Similarly, several genes associated with ALS including TARDBP, FUS, NEK1, SQSTM1 and SETX are known to play a role in DNA repair and the DNA damage response, and thus may contribute to neuronal death via these pathways. Another consistent feature present in both sporadic and familial ALS is the ability of astrocytes to induce motor neuron death, although the factors causing this toxicity remain largely unknown. In this review, we summarise the evidence for DNA damage playing a causative or secondary role in the pathogenesis of ALS as well as discuss the possible mechanisms involved in different genetic subtypes with particular focus on the role of astrocytes initiating or perpetuating DNA damage in neurons.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available