Abstract
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.
Highlights
Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurodegenerative disease presented with progressive pancerebellar ataxia, leading to total disability [1,2,3,4]
We found that the mutation produces an expanded RNA repeat, which aberrantly accumulates in SCA10 cells and interacts with a major RNA–binding protein
We showed that either blocking the expanded AUUCU repeat or replenishing heteronuclear ribonuclear protein K (hnRNP K) rescues cells from the cell death induced by the SCA10 mutation
Summary
Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurodegenerative disease presented with progressive pancerebellar ataxia, leading to total disability [1,2,3,4]. The disease-causing genetic mutation is a large (up to 22.5 kb) expansion of a pentanucleotide, ATTCT, repeat present within the ninth intron of the ATXN10 gene on chromosome 22q13.31 [6]. In the last two decades, investigators identified a group of diseases caused by expansions of short tandem repeats, known as microsatellite repeats. Most of these mutations involve unstable trinucleotide repeats located in different regions of respective genes. Friedreich’s ataxia (FRDA) is the only known disease caused by an expansion of an intronic trinucleotide repeat. Typical FRDA mutations are large GAA repeats located in intron 1 of the FXN gene, which severely hinders the transcription of the FXN gene, leading to the autosomal recessive phenotype [9]
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