ESTUDIO SOBRE LA INTERACCION FUNCIONAL ENTRE AMILINA Y SINUCLEINA IN VIVO. IMPLICACION PARA LA NEURODEGENERACIÓN Y NUEVAS TERAPIAS EN LA ENFERMEDAD DE PARKINSON

PI21/00259

Nombre agencia financiadora Instituto de Salud Carlos III
Acrónimo agencia financiadora ISCIII
Programa Programa Estatal de Generación de Conocimiento y Fortalecimiento del Sistema Español de I+D+I
Subprograma Subprograma Estatal de Generación de Conocimiento
Convocatoria Proyectos de investigación en salud
Año convocatoria 2021
Unidad de gestión Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 (ISCIII)
Centro beneficiario FUNDACION INSTITUTO DE INVESTIGACION SANITARIA DE NAVARRA
Centro realización INSTITUTO DE INVESTIGACION SANITARIA DE NAVARRA (IdISNA)
Identificador persistente https://doi.org/10.13039/501100004587

Publicaciones

Resultados totales (Incluyendo duplicados): 1
Encontrada(s) 1 página(s)

Stabilization of 14-3-3 protein-protein interactions with Fusicoccin-A decreases alpha-synuclein dependent cell-autonomous death in neuronal and mouse models

Academica-e. Repositorio Institucional de la Universidad Pública de Navarra
  • Vinueza-Gavilanes, Rodrigo
  • Bravo-González, Jorge Juan
  • Basurco, Leyre
  • Boncristiani, Chiara
  • Fernández Irigoyen, Joaquín
  • Santamaría Martínez, Enrique
  • Marcilla, Irene
  • Pérez Mediavilla, Alberto
  • Luquin, María Rosario
  • Vales, Africa
  • González-Aseguinolaza, Gloria
  • Aymerich, María Soledad
  • Aragón, Tomás
  • Arrasate, Montserrat
Synucleinopathies are a group of neurodegenerative diseases without effective treatment characterized by the abnormal aggregation of alpha-synuclein (aSyn) protein. Changes in levels or in the amino acid sequence of aSyn (by duplication/triplication of the aSyn gene or point mutations in the encoding region) cause familial cases of synucleinopathies. However, the specific molecular mechanisms of aSyn-dependent toxicity remain unclear. Increased aSyn protein levels or pathological mutations may favor abnormal protein-protein interactions (PPIs) that could either promote neuronal death or belong to a coping response program against neurotoxicity. Therefore, the identification and modulation of aSyn-dependent PPIs can provide new therapeutic targets for these diseases. To identify aSyn-dependent PPIs we performed a proximity biotinylation assay based on the promiscuous biotinylase BioID2. When expressed as a fusion protein, BioID2 biotinylates by proximity stable and transient interacting partners, allowing their identification by streptavidin affinity purification and mass spectrometry. The aSyn interactome was analyzed using BioID2-tagged wild-type (WT) and pathological mutant E46K aSyn versions in HEK293 cells. We found the 14-3-3 epsilon isoform as a common protein interactor for WT and E46K aSyn. 14‐3-3 epsilon correlates with aSyn protein levels in brain regions of a transgenic mouse model overexpressing WT human aSyn. Using a neuronal model in which aSyn cell-autonomous toxicity is quantitatively scored by longitudinal survival analysis, we found that stabilization of 14‐3-3 protein-proteins interactions with Fusicoccin-A (FC-A) decreases aSyn-dependent toxicity. Furthermore, FC-A treatment protects dopaminergic neuronal somas in the substantia nigra of a Parkinson's disease mouse model. Based on these results, we propose that the stabilization of 14‐3-3 epsilon interaction with aSyn might reduce aSyn toxicity, and highlight FC-A as a potential therapeutic compound for synucleinopathies., This work was supported by the Navarra Government (3/2019 , PC060-061 and PC192-193), the Spanish Government ISCIII-FEDER PI20/01063 and PI21/00259 and the Fundación para la Investigación Médica Aplicada (FIMA) . R.V-G was supported by a postdoctoral contract from the Navarra Government (PC192-193), J.B. by the Investigación Biomédica AC 2020 Predoctoral Fellowships from CIMA University of Navarra , C·B was supported by University of Milan with Students Erasmus+ Scholarships a.y. 2018/2019 and L. B. by a FPU predoctoral fellowship FPU018/02244 .