DNA Repair in Huntington’s Disease and Spinocerebellar Ataxias: Somatic Instability and Alternative Hypotheses

Abstract

The use of genome wide association studies (GWAS) in Huntington’s disease (HD) research, driven by unbiased human data analysis, has transformed the focus of new targets that could affect age at onset. While there is a significant depth of information on DNA damage repair, with many drugs and drug targets, most of this development has taken place in the context of cancer therapy. DNA damage repair in neurons does not rely on DNA replication correction mechanisms. However, there is a strong connection between DNA repair and neuronal metabolism, mediated by nucleotide salvaging and the poly ADP-ribose (PAR) response, and this connection has been implicated in other age-onset neurodegenerative diseases. Validation of leads including the mismatch repair protein MSH3, and interstrand cross-link repair protein FAN1, suggest the mechanism is driven by somatic CAG instability, which is supported by the protective effect of CAA substitutions in the CAG tract. We currently do not understand: how somatic instability is triggered; the state of DNA damage within expanding alleles in the brain; whether this damage induces mismatch repair and interstrand cross-link pathways; whether instability mediates toxicity, and how this relates to human ageing. We discuss DNA damage pathways uncovered by HD GWAS, known roles of other polyglutamine disease proteins in DNA damage repair, and a panel of hypotheses for pathogenic mechanisms.

Nuclear and cytoplasmic huntingtin inclusions exhibit distinct biochemical composition, interactome and ultrastructural properties

“…Our data are in line with previous EM studies from human HD patients 95 and HD mice models 19,96 showing nuclear ultrastructural changes, including altered nuclear membrane shape, nuclear invagination and increased nuclear pore density in neurons bearing Httex1 inclusions. Consistent with these observations, the nuclei containing Httex1 72Q inclusions showed enhanced nuclear condensation over time (Figure 5E), indicating increased neuronal toxicity, consistent with previous reports in HD patients 97 and HD mice model 96 . Interestingly, despite the presence of the large inclusions as early as D3 in the neurons overexpressing Δ Nt17 Httex1 72Q, we did not observe an earlier onset of cell death or a higher level of toxicity over time in these neurons compared to those overexpressing Httex1 72Q (Figure 5E).…”

FAN1, a DNA Repair Nuclease, as a Modifier of Repeat Expansion Disorders

“…The requirement of MMR complexes-including MutS␣ (MSH2-MSH3), MutS␤ (MSH2-MSH6), MutL␣ (MLH1-PMS2) and MutL␥ (MLH1-MLH3)-in CAG/CTG, CGG/CCG, and GAA/TTC repeat instability has been extensively studied [185,210,213,[222][223][224][225][226][227][228][229]. MustS␤ (MSH2-MSH3), through its ability to bind slip-DNA structures, may facilitate their formation [210].…”

Approaches to Sequence the HTT CAG Repeat Expansion and Quantify Repeat Length Variation

“…Swami et al [14] investigated somatic expansion in post-mortem DNA samples from HD patients, and showed that patients with particularly early-onset have a higher proportion of large expansions in the cortex. Most recently, genetic association studies in HD patient cohorts have revealed the association between DNA repair gene variants and age at motor signs of HD and HD progression [15][16][17][18][19]. These data suggest that somatic CAG repeat expansions contribute toward HD pathology.…”

“…More detailed quantitative analyses of the dynamics of somatic mosaicism should help to answer some of these questions, and further disentangling of the mechanisms by which they are generated should allow for the identification of additional therapeutic targets. Although several components of the DNA mismatch repair pathway have been shown to be critical for somatic expansion [12,[20][21][22][23], the precise molecular processes that generate expansions and determine their tissue specificity is unknown [18,19,24,25]. In this context, precise and accurate quantification of HTT CAG somatic mosaicism in patient samples and model systems is warranted, since it may provide a suitable phenotype for genetic association studies aimed at identifying genetic variants that act as modifiers of repeat instability [7,15].…”