The central role of DNA damage and repair in CAG repeat diseases

Abstract

Diseases such as Huntington's disease and certain spinocerebellar ataxias are caused by the expansion of genomic cytosine-adenine-guanine (CAG) trinucleotide repeats beyond a specific threshold. These diseases are all characterised by neurological symptoms and central neurodegeneration, but our understanding of how expanded repeats drive neuronal loss is incomplete. Recent human genetic evidence implicates DNA repair pathways, especially mismatch repair, in modifying the onset and progression of CAG repeat diseases. Repair pathways might operate directly on repeat sequences by licensing or inhibiting repeat expansion in neurons. Alternatively, or in addition, because many of the genes containing pathogenic CAG repeats encode proteins that themselves have roles in the DNA damage response, it is possible that repeat expansions impair specific DNA repair pathways. DNA damage could then accrue in neurons, leading to further expansion at repeat loci, thus setting up a vicious cycle of pathology. In this review, we consider DNA damage and repair pathways in postmitotic neurons in the context of disease-causing CAG repeats. Investigating and understanding these pathways, which are clearly relevant in promoting and ameliorating disease in humans, is a research priority, as they are known to modify disease and therefore constitute prevalidated drug targets.

One decade ago, one decade ahead in huntington's disease

“…Defective DNA mismatch repair, which can be contributed to by heritable genetic modifiers, is increasingly seen as the likely culprit behind such expansions. 42,43 Two individuals with the same CAG repeat length, say 42, on the standardized HD predictive genetic test performed on blood might have wildly discrepant ages of onset. Much of that difference may well be explained by the brain of the younger-onset individual containing many neurons with a true CAG of 80 or 150, whereas those of the more fortunate individual may only have expanded a little or not at all.…”

DNA repair in trinucleotide repeat ataxias

“…Subsequently, genotyping of these single nucleotide polymorphisms (SNP) in patients with CAG repeat disease (consisting of 1017 SCA patients), showed a significant association between DNA repair genes and the age at onset of SCA and HD, with SNPs in FAN1, PMS2 and RRM2B reaching the lowest Pvalues [30]. These findings suggest that common DNA repair pathways act on TNR expansion modifying expression [31,32]. neurogenesis, particularly the proliferative expansion phase [33].…”

“…A recent review by Holmans et al provides an excellent summary in the identification of genetic modifiers [5]. These findings suggest that common DNA repair pathways act on TNR expansion modifying expression [31,32]. GWAS are an effective way to identify such common variants [29], but achieving sufficient power for rare conditions is challenging.…”

“…These findings suggest that common DNA repair pathways act on TNR expansion modifying expression [31,32]. These genes synthesize end-processing enzymes pivotal to SSB repair, and also play an important role in the repair of DSB by the nonhomologous end joining pathway [31,42,43]. Similarly, deficient DNA repair in the mature brain is associated with ageing and neurodegenerative conditions such as Alzheimer's disease [34].…”

“…Notably, Ataxia-ocular motor apraxia 1 [39], SCA with axonal neuropathy 1 [40], and Ataxia-ocular motor apraxia 4 [41], occur due to mutations in APTX, TDP1 and PNKP, respectively. These genes synthesize end-processing enzymes pivotal to SSB repair, and also play an important role in the repair of DSB by the nonhomologous end joining pathway [31,42,43]. Similarly, in TNR disorders such as SCAs, DNA repair regulation is an essential process to maintain integrity of expansions in replication and translation [21,44].…”