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Updated: Dec 18, 2025
Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
Pathogenic SREK1 decrease in Huntington's disease lowers TAF1 mimicking X-linked dystonia parkinsonism
Ivó H Hernández1,2,3, Jorge R Cabrera1,2, María Santos-Galindo1,2
1Center for Molecular Biology 'Severo Ochoa' (CBMSO) CSIC/UAM, Madrid 28049, Spain.
Insights
Huntington's disease and X-linked dystonia parkinsonism share a common pathway involving altered RNA processing and TAF1 gene expression. Restoring SREK1 levels can correct TAF1 deficiency and ameliorate Huntington's disease symptoms.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Huntington's disease (HD) and X-linked dystonia parkinsonism (XDP) are basal ganglia disorders caused by genetic mutations.
- HD involves CAG repeat expansion in the Huntingtin (HTT) gene, leading to toxic protein and mRNA interactions.
- XDP results from a TAF1 gene mutation, decreasing its expression and affecting the TFIID transcription factor complex.
Purpose of the Study:
- To investigate a potential convergence in the pathogenesis of HD and XDP.
- To explore the role of RNA-binding proteins SRSF6 and SREK1 in these diseases.
- To determine if TAF1 is a common link and therapeutic target.
Main Methods:
- RNA interference (RNAi) to diminish SRSF6 in neuroblastoma cells.
- Analysis of SREK1 and TAF1 levels in patient and mouse models.
- Generation of transgenic mice overexpressing SREK1 (TgSREK1).
- Transcriptomic analysis and phenotypic evaluation of mouse models.
Main Results:
- Diminishing SRSF6 reduced SREK1 levels, which in turn decreased TAF1 levels.
- Decreased SREK1 and TAF1 levels were observed in HD patient striatum and mouse models.
- TgSREK1 mice exhibited transcriptomic changes complementary to HD mice.
- SREK1 overexpression corrected TAF1 deficiency and attenuated HD phenotypes in mice.
Conclusions:
- Altered RNA processing due to SREK1 dysregulation is crucial in HD pathogenesis.
- TAF1 deficiency is a key factor in striatal vulnerability in neurological disorders.
- SREK1 represents a potential therapeutic target for HD and possibly other basal ganglia diseases.
Abstract:
Huntington's disease and X-linked dystonia parkinsonism are two monogenic basal ganglia model diseases. Huntington's disease is caused by a polyglutamine-encoding CAG repeat expansion in the Huntingtin (HTT) gene leading to several toxic interactions of both the expanded CAG-containing mRNA and the polyglutamine-containing protein, while X-linked dystonia parkinsonism is caused by a retrotransposon insertion in the TAF1 gene, which decreases expression of this core scaffold of the basal transcription factor complex TFIID. SRSF6 is an RNA-binding protein of the serine and arginine-rich (SR) protein family that interacts with expanded CAG mRNA and is sequestered into the characteristic polyglutamine-containing inclusion bodies of Huntington's disease brains. Here we report decreased levels of the SRSF6 interactor and regulator SREK1-another SR protein involved in RNA processing-which includes TAF1 as one of its targets. This led us to hypothesize that Huntington's disease and X-linked dystonia parkinsonism pathogeneses converge in TAF1 alteration. We show that diminishing SRSF6 through RNA interference in human neuroblastoma cells leads to a decrease in SREK1 levels, which, in turn, suffices to cause diminished TAF1 levels. We also observed decreased SREK1 and TAF1 levels in striatum of Huntington's disease patients and transgenic model mice. We then generated mice with neuronal transgenic expression of SREK1 (TgSREK1 mice) that, interestingly, showed transcriptomic alterations complementary to those in Huntington's disease mice. Most importantly, by combining Huntington's disease and TgSREK1 mice we verify that SREK1 overexpression corrects TAF1 deficiency and attenuates striatal atrophy and motor phenotype of Huntington's disease mice. Our results therefore demonstrate that altered RNA processing upon SREK1 dysregulation plays a key role in Huntington's disease pathogenesis and pinpoint TAF1 as a likely general determinant of selective vulnerability of the striatum in multiple neurological disorders.
