Pathogenic SREK1 decrease in Huntington's disease lowers TAF1 mimicking X-linked dystonia parkinsonism

Brain : a Journal of Neurology
Ivó H HernándezJosé J Lucas

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 al...Continue Reading

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Citations

Sep 23, 2020·Movement Disorders : Official Journal of the Movement Disorder Society·Sokhna Haissatou Diaw, Katja Lohmann
Jun 3, 2021·International Journal of Molecular Sciences·Chisato KinoshitaKoji Aoyama
Mar 17, 2021·Brain : a Journal of Neurology·Ainara ElorzaJosé J Lucas
Jan 15, 2022·Journal of Extracellular Vesicles·Xiaoyu YuHonghong Yao

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Methods Mentioned

BETA
transfection
Protein Assay
Assay
RNA-seq
transgenic

Software Mentioned

ImageJ
VAST
- TOOLS
Tools
GSEA
Real Time Analysis ( RTA
SPSS

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