GAA•TTC repeat expansion in human cells is mediated by mismatch repair complex MutLγ and depends upon the endonuclease domain in MLH3 isoform one.

DNA repeat expansion underlies dozens of progressive neurodegenerative disorders. While the mechanisms driving repeat expansion are not fully understood, increasing evidence suggests a central role for DNA mismatch repair. The mismatch repair recognition complex MutSβ (MSH2-MSH3) that binds mismatched bases and/or insertion/deletion loops has previously been implicated in GAA•TTC, CAG•CTG and CGG•CCG repeat expansion, suggesting a shared mechanism.

DNA mismatch repair complex MutSβ promotes GAA·TTC repeat expansion in human cells.

While DNA repair has been implicated in CAG·CTG repeat expansion, its role in the GAA·TTC expansion of Friedreich ataxia (FRDA) is less clear. We have developed a human cellular model that recapitulates the DNA repeat expansion found in FRDA patient tissues. In this model, GAA·TTC repeats expand incrementally and continuously.

Patterns of striatal degeneration in frontotemporal dementia.

Behavioral variant frontotemporal dementia and semantic dementia have been associated with striatal degeneration, but few studies have delineated striatal subregion volumes in vivo or related them to the clinical phenotype. We traced caudate, putamen, and nucleus accumbens on magnetic resonance images to quantify volumes of these structures in behavioral variant frontotemporal dementia, semantic dementia, Alzheimer disease, and healthy controls (n=12 per group). We further related these striatal volumes to clinical deficits and neuropathologic findings in a subset of patients.