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Título: | Glycogen synthase kinase-3 plays a crucial role in tau exon 10 splicing and intranuclear distribution of SC35: Implications for Alzheimer's disease |
Autor: | Hernández, Félix; Pérez, Mar CSIC ORCID; Lucas, José Javier CSIC ORCID; Mata, Ana M.; Bhat, Ratan; Ávila, Jesús CSIC ORCID | Fecha de publicación: | 2004 | Editor: | Elsevier | Citación: | Journal of Biological Chemistry 279(5): 3801-3806 (2004) | Resumen: | Tauopathies, including Alzheimer's disease, are neurodegenerative disorders in which tau protein accumulates as a consequence of alterations in its metabolism. At least three different types of alterations have been described; in some cases, an aberrant mRNA splicing of tau exon 10 occurs; in other cases, the disorder is a consequence of missense mutations and, in most cases, aberrant tau hyperphosphorylation takes place. Glycogen synthase kinase-3 (GSK-3) has emerged as a key kinase that is able to interact with several proteins involved in the ethiology of Alzheimer's disease and other tauopathies. Here, we have evaluated whether GSK-3 is also able to modulate tau-mRNA splicing. Our data demonstrate that GSK-3 inhibition in cultured neurons affects tau splicing resulting in an increase in tau mRNA containing exon 10. Pre-mRNA splicing is catalyzed by a multimolecular complex including members of the serine/arginine-rich (SR) family of splicing factors. Immunofluorescence studies showed that after GSK-3 inhibition, SC35, a member of the SR family, is redistributed and enriched in nuclear speckles and colocalizes with the kinase. Furthermore, immunoprecipitated SC35 is phosphorylated by recombinant GSK-3β. Phosphorylation of a peptide from the SR domain by GSK-3 revealed that the peptide needs to be prephosphorylated, suggesting the involvement of a priming kinase. Our results demonstrate that GSK-3 plays a crucial role in tau exon 10 splicing, raising the possibility that GSK3 could contribute to tauopathies via aberrant tau splicing. | Versión del editor: | https://doi.org/10.1074/jbc.M311512200 | URI: | http://hdl.handle.net/10261/252259 | DOI: | 10.1074/jbc.M311512200 | ISSN: | 0021-9258 |
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