Pathogenic SREK1 decrease in Huntington's disease lowers TAF1 mimicking X-linked dystonia parkinsonism
| Autor: | Manuel Sánchez-Martín, Belén Pintado, José J. Lucas, Maria Jose Perez-Alvarez, Ramón García-Escudero, Verónica Domínguez, Ivó H. Hernández, María Santos-Galindo, Jorge Rubén Cabrera |
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| Přispěvatelé: | Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Fundación Ramón Areces |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
congenital hereditary and neonatal diseases and abnormalities medicine.medical_specialty Huntingtin SREK1 Mice Transgenic Biology X-Linked Dystonia Parkinsonism Splicing RNA-binding proteins (RBP) 03 medical and health sciences Mice 0302 clinical medicine Huntington's disease RNA interference Internal medicine mental disorders Basal ganglia medicine Animals Humans TAF1 Histone Acetyltransferases Dystonia TATA-Binding Protein Associated Factors Serine-Arginine Splicing Factors Genetic Diseases X-Linked medicine.disease Phosphoproteins nervous system diseases 030104 developmental biology Endocrinology Huntington Disease Dystonic Disorders Transcription Factor TFIID Neurology (clinical) Trinucleotide repeat expansion 030217 neurology & neurosurgery SR proteins |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| ISSN: | 2015-6537 |
| Popis: | The Author(s) (2020). 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. This work was supported by CIBERNED-ISCIII collaborative grants PI2015-2/06-3 and PI2018/06-1 and by grants from Spanish Ministry of Economy and Competitiveness/Ministry of Science, Innovation and Universities (MINECO/MCIU/AEI/FEDER, UE): SAF2015-65371-R and RTI2018-096322-B-I00 to J.J.L. and PI18/00263 from the Instituto de Salud Carlos III (Ministry of Economy, Industry and Competitiveness)—cofunded by the European Regional Development Fund—to R.G.-E. and by institutional grant from Fundación Ramón Areces to CBMSO. |
| Databáze: | OpenAIRE |
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