Abstract
Friedreich ataxia (FRDA) is a progressive neurodegenerative disease caused by GAA•TTC repeat expansion. Understanding the mechanisms by which repeat expansion occurs may reveal therapeutic targets that will enable us to slow FRDA progression and delay or even prevent FRDA onset. We have previously shown that the mismatch repair (MMR) complex MutSbeta, plays an important role in the expansion process. However, it is not known if expansion results from an aberrant side reaction mediated by MutSbeta, or from an otherwise normal MMR response. Typically, in MMR, MutS heterodimers recognize a mismatch but a MutL heterodimer is required for the next step. In humans there are four identified MutL heterodimers, with MLH1 as the master subunit in all of them. Therefore, to determine if appropriate downstream MMR processing is involved in GAA•TTC repeat expansion we targeted MLH1 for knockdown in our system. We report here that MLH1 knockdown studies show a role for MLH1 in GAA•TTC expansion. Our data suggest that GAA•TTC repeat expansion may represent an unfortunate outcome of normally functioning MMR. Funded by grants from the NIH (F30AG042263 to AH), the Friedreich's Ataxia Research Alliance and the LSUHSC Research Enhancement Fund to EG.
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