DNA Damage, Defective DNA Repair, and Neurodegeneration in Amyotrophic Lateral Sclerosis

Abstract

DNA is under constant attack from both endogenous and exogenous sources, and when damaged, specific cellular signalling pathways respond, collectively termed the “DNA damage response.” Efficient DNA repair processes are essential for cellular viability, although they decline significantly during aging. Not surprisingly, DNA damage and defective DNA repair are now increasingly implicated in age-related neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). ALS affects both upper and lower motor neurons in the brain, brainstem and spinal cord, leading to muscle wasting due to denervation. DNA damage is increasingly implicated in the pathophysiology of ALS, and interestingly, the number of DNA damage or repair proteins linked to ALS is steadily growing. This includes TAR DNA binding protein 43 (TDP-43), a DNA/RNA binding protein that is present in a pathological form in almost all (97%) cases of ALS. Hence TDP-43 pathology is central to neurodegeneration in this condition. Fused in Sarcoma (FUS) bears structural and functional similarities to TDP-43 and it also functions in DNA repair. Chromosome 9 open reading frame 72 (C9orf72) is also fundamental to ALS because mutations in C9orf72 are the most frequent genetic cause of both ALS and related condition frontotemporal dementia, in European and North American populations. Genetic variants encoding other proteins involved in the DNA damage response (DDR) have also been described in ALS, including FUS, SOD1, SETX, VCP, CCNF, and NEK1. Here we review recent evidence highlighting DNA damage and defective DNA repair as an important mechanism linked to neurodegeneration in ALS.

Meta-analysis of the amyotrophic lateral sclerosis spectrum uncovers genome instability

“…ALS motor neurons showed altered splicing in neuronal genes as well as greater numbers of SNVs, indels and gene fusions compared to controls, which may contribute to the elevated DNA damage response. Our findings add to a growing body of evidence for the role of defective DNA repair and induction of the DNA damage response in ALS motor neurons 45 .…”

Integrated transcriptome landscape of ALS identifies genome instability linked to TDP-43 pathology

“…This was combined with the accumulation of somatic mutations and gene fusions, which may contribute to the elevated DNA damage response. Our findings add to the growing body of evidence implicating defective DNA damage repair and induction of the DNA damage response in ALS 58 .…”

Rare variant analyses validate known ALS genes in a multi-ethnic population and identifiesANTXR2as a candidate in PLS

“…Control-enrichment was not explained by sequencing methodology, ancestry cluster, or specific phenotype/disease population within the control cohort. Because ALKBH3 plays a role in DNA repair(22), a mechanism increasingly implicated in ALS pathogenesis(23), we attempted to replicate this novel association by analyzing summary statistics from the Project MinE cohort, which is similar in size to ours (24). None of the available models focused on variation as rare as in our analyses, but at a higher minor allele frequency (MAF) for qualifying variants (0.005), a minor degree of control-enrichment was in fact observed (OR= 0.56, p = 3.96 × 10 −4 ).…”