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We present a unique thirty-nine year old woman with both Huntington's disease (HD) and spinocerebellar ataxia type 10 (SCA10). She has 48 CAG repeats in the HD gene and 2511 ATTCT repeats in the ATX10 gene. Although both conditions are repeat expansion diseases they are thought to have quite different pathogenic mechanisms. The symptomatic age of onset in this patient (mid30s) is within the expected range for her repeat expansion sizes for each condition, but we discuss the evidence that the two conditions may interact to produce a more severe cognitive phenotype than would be expected for either of the conditions independently. The subject has Amerindian background on the maternal side from Colombia, South America, thus adding a 5th country expressing SCA10, all with Amerindian ancestry.

We have identified a large expansion of an ATTCT repeat within intron 9 of ATXN10 on chromosome 22q13.31 as the genetic mutation of spinocerebellar ataxia type 10 (SCA10). Our subsequent studies indicated that neither a gain nor a loss of function of ataxin 10 is likely the major pathogenic mechanism of SCA10. Here, using SCA10 cells, and transfected cells and transgenic mouse brain expressing expanded intronic AUUCU repeats as disease models, we show evidence for a key pathogenic molecular mechanism of SCA10. First, we studied the fate of the mutant repeat RNA by in situ hybridization. A Cy3-(AGAAU)10 riboprobe detected expanded AUUCU repeats aggregated in foci in SCA10 cells. Pull-down and co-immunoprecipitation data suggested that expanded AUUCU repeats within the spliced intronic sequence strongly bind to hnRNP K. Co-localization of hnRNP K and the AUUCU repeat aggregates in the transgenic mouse brain and transfected cells confirmed this interaction. To examine the impact of this interaction on hnRNP K function, we performed RT–PCR analysis of a splicing-regulatory target of hnRNP K, and found diminished hnRNP K activity in SCA10 cells. Cells expressing expanded AUUCU repeats underwent apoptosis, which accompanied massive translocation of PKCδ to mitochondria and activation of caspase 3. Importantly, siRNA–mediated hnRNP K deficiency also caused the same apoptotic event in otherwise normal cells, and over-expression of hnRNP K rescued cells expressing expanded AUUCU repeats from apoptosis, suggesting that the loss of function of hnRNP K plays a key role in cell death of SCA10. These results suggest that the expanded AUUCU–repeat in the intronic RNA undergoes normal transcription and splicing, but causes apoptosis via an activation cascade involving a loss of hnRNP K activities, massive translocation of PKCδ to mitochondria, and caspase 3 activation., Author Summary In an earlier study, we showed that the mutation of spinocerebellar ataxia 10 (SCA10) is an enormous expansion of a gene segment, which contains a tandemly repeated 5-base (ATTCT) unit. Since SCA10 is the only known human disease that is proven to be caused by 5-base repeat expansion, it is important to learn how this novel class of mutation causes the disease. We found that the mutation produces an expanded RNA repeat, which aberrantly accumulates in SCA10 cells and interacts with a major RNA–binding protein. When we expressed expanded RNA repeats or decreased the RNA–binding protein level in cultured cells, either of these manipulations produced a specific type of cell death that is associated with a massive transfer of a key enzyme called protein kinase C delta to mitochondria. We also showed that either blocking the expanded AUUCU repeat or replenishing hnRNP K rescues cells from the cell death induced by the SCA10 mutation. Together, we conclude that the mutant RNA inactivates hnRNP K and kills cells by triggering the specific cell-death mechanism. Our data provide important clues for therapeutic intervention in SCA10.