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 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 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 augments 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.

Neurodevelopmental Clues to Neurodegeneration

“…The motor dysfunction can include dystonia, bradykinesia, and rigidity in addition to chorea. 43  Pathologically, Huntington disease is characterized by a loss of striatal volume, primarily due to apoptosis of medium spiny neurons. Cerebral cortical volume loss is common as well.…”

Inhibition of heat shock proteins increases autophagosome formation, and reduces the expression of APP, Tau, SOD1 G93A and TDP-43

“…The pathologies Alzheimer’s Disease (AD), familial Amyotrophic Lateral Sclerosis (ALS) and Huntington’s Chorea (HC) are all in part mediated by the aberrant expression and denaturation of disease-specific proteins [ 1 – 6 ]. In AD, amyloid-β and Tau proteins form toxic aggregates inside neurons and in the extracellular environment.…”

The Startling Role of Mismatch Repair in Trinucleotide Repeat Expansions

“…However, some important differences with non-expandable microsatellites are noteworthy: (i) a strong bias toward expansions compared to contractions; (ii) the critical role of MutSβ compared to MutSα, suggesting that large mismatches are the rule; and (iii) the frequent occurrence of mixed progeny, suggesting that hairpin-containing heteroduplex DNA frequently escapes repair. Present models propose that expansions occur if the old strand is repaired using the newly synthesized strand as a template, generating a small expansion whose size is equal to the length of the hairpin ( Figure 1 ) [ 79 , 87 ]. Conversely, if the new strand is fixed using the old one as a template, no size change occurs.…”

“…In conclusion, experiments in yeast, mice, and human cells, as well as GWAS data, all point to a role of MMR proteins in trinucleotide repeat expansions by a mechanism that seems to be unrelated to classical strand slippage during the replication of non-expandable microsatellites [ 79 ].…”