Elucidation of disease-related protein networks underlying dyrk1a overexpression and pro-cognitive therapies in the hippocampus

• Autores: Mireia Ortega
• Directores de la Tesis: Mara Dierssen Sotos (dir. tes.), Eduard Sabidó Aguadé (codir. tes.)
• Lectura: En la Universitat Pompeu Fabra ( España ) en 2018
• Idioma: español
• Tribunal Calificador de la Tesis: Francesc Canals Suris (presid.), Jordi García-Ojalvo (secret.), Cedric Boeckx (voc.)
• Programa de doctorado: Programa de Doctorado en Biomedicina por la Universidad Pompeu Fabra
• Materias:
  • Química
    • Química analítica
      • Espectroscopia de masas
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• Resumen

  • Down syndrome (DS) is the most frequent genetic cause of intellectual disability. It is a multifaceted condition characterized by impairments in cognition, communication, behavior and/or motor skills resulting from abnormal brain development and function. Although DS is caused by the trisomy with more than 300 triplicated genes located on chromosome 21, there are a reduced number of dosage-sensitive candidate genes that play a critical role in the pathogenesis of the disorder.

    Our group has made important contributions demonstrating that overexpression of a single gene, DYRK1A, is sufficient and necessary to recapitulate some of the DS phenotypes. Importantly, we could also demonstrate that the genetic, pharmacological or environmental normalization of its overdosage rescues behavioral, cognitive and neuronal phenotypes in preclinical studies with DS mouse models and in clinical trials in humans.

    In this Thesis I propose that the consequences of DYRK1A overexpression could spread along a complex intracellular network leading to a disease-causing network. For this reason, DYRK1A kinase normalization could be a good molecular target to restore the protein network functionality in DS.

    Here we have examined large-scale protein and phosphoprotein profiling to explore alterations caused by Dyrk1A overexpression and of pro-cognitive therapeutic strategies previously shown in the laboratory to normalize DYRK1A kinase activity and to promote cognition: i) environmental enrichment (EE), ii) and (-)-epigallocatechin-3-gallate (EGCG) and iii) the combination of both EGCG+EE. Using high-throughput tandem mass spectrometry (LC-MS/MS) in the hippocampus of TgDyrk1A mice we show that Dyrk1A overexpression in mice hippocampus primarily affects MAPK signaling and plasticity processes that could be related with impairments in recognition memory. Treatment with EGCG, EE, or their combination (EGCG+EE) restore some of the proteome and phosphoproteome alterations of Dyrk1A overexpression, possibly through the same mechanisms.