Marcilla, I. (Irene)
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- The number of dopaminergic cells is increased in the olfactory bulb of monkeys chronically exposed to MPTP(Wiley Blackwell, 2007) San-Sebastian, W. (Waldy); Garrido-Gil, P. (P.); Lanciego, J.L. (José Luis); Vazquez-Claverie, M. (Marianne); Marcilla, I. (Irene); Belzunegui, S. (S.); Izal-Azcarate, A. (A.); Luquin, M.R. (María Rosario); Lopez, B. (Berta)We investigated the impact of the nigrostriatal lesion on the olfactory tyrosine hydroxylase-immunoreactive (TH-ir) cells in monkeys. The majority of these TH-ir cells appeared in the glomerular layer of the olfactory bulb and many were immature but functional dopaminergic neurons. In parkinsonian monkeys the number of olfactory dopaminergic neurons increased up to 100% as compared to controls, but their phenotype did not change. This increased TH-ir cell population might be a direct consequence of the nigral cell loss and contribute to the hyposmia reported by Parkinson's disease patients.
- Isolation, culture and characterization of adult carotid body-derived cells(Elsevier, 2009) San-Sebastian, W. (Waldy); Gutierrez-Perez, M. (María); Izal-Azcárate, I. (Íñigo); Marcilla, I. (Irene); Belzunegui, S. (S.); Izal-Azcarate, A. (A.); Luquin, M.R. (María Rosario); Prosper-Cardoso, F. (Felipe); Lopez, B. (Berta)Recent studies indicate that carotid body (CB) could be a suitable cell source for cell therapy in Parkinson’s disease.We have isolated and successfully expanded in culture as monolayer adult CB-derived cells using a modification of the culture medium employed for bone marrow multipotent adult progenitor cells (MAPCs). These cells express variable amounts of tyrosine hydroxylase (TH), -III tubulin and Sox2. In addition, CB-derived cells showed high expression of Sox2 related to a high rate of proliferation and consistent with an undifferentiated state. Under culture conditions that reduced cell proliferation, Sox2 expression decreased while TH and -III tubulin expression was increased. This could indicate that the differentiation of some cells occurs in the culture, thus accounting for a certain neural differentiation potential of CB-derived cells.
- Stabilization of 14-3-3 protein-protein interactions with Fusicoccin-A decreases alpha-synuclein dependent cell-autonomous death in neuronal and mouse models(Elsevier, 2023) Aymerich, M.S. (María S.); González-Aseguinolaza, G. (Gloria); Perez-Mediavilla, L.A. (Luis Alberto); Vales, A. (África); Fernandez-Irigoyen, J. (Joaquín); Boncristiani, C. (Chiara); Bravo-González, J.J. (Jorge Juan); Basurco, L. (Leyre); Aragón, T. (Tomás); Marcilla, I. (Irene); Arrasate, M. (Montserrat); Luquin, M.R. (María Rosario); Santamaria, E. (Enrique); Vinueza-Gavilanes, R. (Rodrigo)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.
- Stabilization of 14-3-3 protein-protein interactions with fusicoccin-A decreases alpha-synuclein dependent cell-autonomous death in neuronal and mouse models(2023) Aymerich, M.S. (María S.); González-Aseguinolaza, G. (Gloria); Perez-Mediavilla, L.A. (Luis Alberto); Vales, A. (África); Aragón-Amonárriz, T. (Tomás); Fernandez-Irigoyen, J. (Joaquín); Boncristiani, C. (Chiara); Bravo-González, J.J. (Jorge Juan); Basurco, L. (Leyre); Marcilla, I. (Irene); Arrasate, M. (Montserrat); Santamaria, E. (Enrique); Luquin-Piudo, M.R. (María Rosario); Vinueza-Gavilanes, R. (Rodrigo)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.