New developments in Huntington's disease and other triplet repeat diseases: DNA repair turns to the dark side

Abstract

Huntington's disease (HD) is a fatal, inherited neurodegenerative disease that causes neuronal death, particularly in medium spiny neurons. HD leads to serious and progressive motor, cognitive and psychiatric symptoms. Its genetic basis is an expansion of the CAG triplet repeat in the HTT gene, leading to extra glutamines in the huntingtin protein. HD is one of nine genetic diseases in this polyglutamine (polyQ) category, that also includes a number of inherited spinocerebellar ataxias (SCAs). Traditionally it has been assumed that HD age of onset and disease progression were solely the outcome of age-dependent exposure of neurons to toxic effects of the inherited mutant huntingtin protein. However, recent genome-wide association studies (GWAS) have revealed significant effects of genetic variants outside of HTT. Surprisingly, these variants turn out to be mostly in genes encoding DNA repair factors, suggesting that at least some disease modulation occurs at the level of the HTT DNA itself. These DNA repair proteins are known from model systems to promote ongoing somatic CAG repeat expansions in tissues affected by HD. Thus, for triplet repeats, some DNA repair proteins seem to abandon their normal genoprotective roles and, instead, drive expansions and accelerate disease. One attractive hypothesis-still to be proven rigorously-is that somatic HTT expansions augment the disease burden of the inherited allele. If so, therapeutic approaches that lower levels of huntingtin protein may need blending with additional therapies that reduce levels of somatic CAG repeat expansions to achieve maximal effect.

Keywords: DNA synthesis and repair; genome integrity; mutation; neurodegeneration.

Figure 1. Models for neuronal death and HD

(A) Traditional viewpoint of HD: inherited allele expresses mutant huntingtin protein. With age, neurons die due to toxic effect of mutant huntingtin. (B) New model. In addition to (A), ongoing somatic expansions add to toxic burden in neurons and other brain cells.

Figure 2. DNA repair genes and their proteins identified by GWAS

Figure 3. Model for how non-canonical DNA MMR could drive expansions

(A) A simplified scheme for how normal MMR correctly repairs ‘top’ strand to remove replication error. Ovals, MutSβ subunits Msh2 (green) and Msh3 (blue). Rectangles, MutL homolog subunits Mlh1 (yellow) and either Pms2 or Mlh3 (grey). (B) Hypothetical scheme for how non-canonical MMR aberrantly repairs ‘bottom’ strand to cause expansion.

Figure 4. Potential therapies against HD

Therapy 1 involves huntingtin lowering strategies. Therapy 2 seeks to inhibit specific DNA repair factors to reduce somatic CAG repeat expansions.