ArticlePLoS genetics2010
Inactivation of hnRNP K by expanded intronic AUUCU repeat induces apoptosis via translocation of PKCdelta to mitochondria in spinocerebellar ataxia 10.
Article in PLoS genetics, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 74 papers.
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Who cites it
74 citing papers in PubMed, 111 citations in OpenAlex.
- Starvation-induced HSC70 O-GlcNAcylation activates chaperone-mediated autophagy.The Journal of biological chemistry · 2026Article
- Tandem repeats in human brain evolution and disease susceptibility.Molecules and cells · 2026Review
- Embryonic spinocerebellar ataxia type 37-associated AUUUC repeat RNA causes neurodevelopmental defects.Disease models & mechanisms · 2026Article
- Prion propagation is controlled by a hierarchical network involving the nuclear Tfap2c and hnRNP K factors and the cytosolic mTORC1 complex.PLoS pathogens · 2026Article
- HIF-2α Interaction with Ataxin-10 Enhances HIF-2α Binding to Its Target Gene Promoters.International journal of molecular sciences · 2025Article
- RNA structure in alternative splicing regulation: from mechanism to therapy.Acta biochimica et biophysica Sinica · 2024Review
- Review
- Repeat-associated non-AUG translation induces cytoplasmic aggregation of CAG repeat-containing RNAs.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- ATTCT and ATTCC repeat expansions in the ATXN10 gene affect disease penetrance of spinocerebellar ataxia type 10.HGG advances · 2022Article
- Mechanistic and Therapeutic Insights into Ataxic Disorders with Pentanucleotide Expansions.Cells · 2022Review
- Review
- New spinocerebellar ataxia subtype caused byBrain communications · 2022Article
- The genetic and molecular features of the intronic pentanucleotide repeat expansion in spinocerebellar ataxia type 10.Frontiers in genetics · 2022Review
- Computational Investigation of Bending Properties of RNA AUUCU, CCUG, CAG, and CUG Repeat Expansions Associated With Neuromuscular Disorders.Frontiers in molecular biosciences · 2022Article
- Molecular mechanisms underlying nucleotide repeat expansion disorders.Nature reviews. Molecular cell biology · 2021Review
- DNAzyme Cleavage of CAG Repeat RNA in Polyglutamine Diseases.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2021Article
- Ataxin-10 Inhibits TNF-Mediators of inflammation · 2021Article
- Stress granule subtypes: an emerging link to neurodegeneration.Cellular and molecular life sciences : CMLS · 2020Review
- Abnormal scaffold attachment factor 1 expression and localization in spinocerebellar ataxias and Huntington's chorea.Brain pathology (Zurich, Switzerland) · 2020Article
- Small molecule targeting of RNA structures in neurological disorders.Annals of the New York Academy of Sciences · 2020Review
14 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 4 institutions in 2 countries.
Funding
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 PKCdelta 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 PKCdelta to mitochondria, and caspase 3 activation.
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