National Institute for Translational Neuroscience

São Paulo, Brazil

National Institute for Translational Neuroscience

São Paulo, Brazil

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Hajj G.N.M.,Ac Camargo Hospital | Hajj G.N.M.,National Institute for Translational Neuroscience | Arantes C.P.,University of Sao Paulo | Dias M.V.S.,Ac Camargo Hospital | And 14 more authors.
Cellular and Molecular Life Sciences | Year: 2013

The co-chaperone stress-inducible protein 1 (STI1) is released by astrocytes, and has important neurotrophic properties upon binding to prion protein (PrPC). However, STI1 lacks a signal peptide and pharmacological approaches pointed that it does not follow a classical secretion mechanism. Ultracentrifugation, size exclusion chromatography, electron microscopy, vesicle labeling, and particle tracking analysis were used to identify three major types of extracellular vesicles (EVs) released from astrocytes with sizes ranging from 20-50, 100-200, and 300-400 nm. These EVs carry STI1 and present many exosomal markers, even though only a subpopulation had the typical exosomal morphology. The only protein, from those evaluated here, present exclusively in vesicles that have exosomal morphology was PrP C. STI1 partially co-localized with Rab5 and Rab7 in endosomal compartments, and a dominant-negative for vacuolar protein sorting 4A (VPS4A), required for formation of multivesicular bodies (MVBs), impaired EV and STI1 release. Flow cytometry and PK digestion demonstrated that STI1 localized to the outer leaflet of EVs, and its association with EVs greatly increased STI1 activity upon PrPC-dependent neuronal signaling. These results indicate that astrocytes secrete a diverse population of EVs derived from MVBs that contain STI1 and suggest that the interaction between EVs and neuronal surface components enhances STI1-PrPC signaling. © 2013 Springer Basel.


De Souza L.E.R.,Federal University of Paraná | Moura Costa M.D.,Federal University of Paraná | Bilek E.S.,Federal University of Paraná | Lopes M.H.,University of Sao Paulo | And 6 more authors.
Experimental Cell Research | Year: 2014

Rnd proteins comprise a branch of the Rho family of small GTP-binding proteins, which have been implicated in rearrangements of the actin cytoskeleton and microtubule dynamics. Particularly in the nervous system, Rnd family proteins regulate neurite formation, dendrite development and axonal branching. A secreted form of the co-chaperone Stress-Inducible Protein 1 (STI1) has been described as a prion protein partner that is involved in several processes of the nervous system, such as neurite outgrowth, neuroprotection, astrocyte development, and the self-renewal of neural progenitor cells. We show that cytoplasmic STI1 directly interacts with the GTPase Rnd1. This interaction is specific for the Rnd1 member of the Rnd family. In the COS collapse assay, overexpression of STI1 prevents Rnd1-plexin-A1-mediated cytoskeleton retraction. In PC-12 cells, overexpression of STI1 enhances neurite outgrowth in cellular processes initially established by Rnd1. Therefore, we propose that STI1 participates in Rnd1-induced signal transduction pathways that are involved in the dynamics of the actin cytoskeleton. © 2014.


Cunha A.M.,Federal University of Rio de Janeiro | Cunha A.M.,State University of Rio de Janeiro | Nascimento F.S.,Federal University of Rio de Janeiro | Amaral J.C.O.F.,Federal University of Rio de Janeiro | And 6 more authors.
Arquivos de Neuro-Psiquiatria | Year: 2011

Several animal experimental models have been used in the study of malignant gliomas. The objective of the study was to test the efficacy of a simple, reproducible and low cost animal model, using human cells of glioblastoma multiforme (GBM) xenotransplantated in subcutaneous tissue of Wistar rats, immunosuppressed with cyclosporin given by orogastric administration, controlled by nonimunosuppressed rats. The animals were sacrificed at weekly intervals and we have observed gradual growth of tumor in the immunosuppressed group. The average tumor volume throughout the experiment was 4.38 cm3 in the immunosuppressed group, and 0.27 cm3 in the control one (p<0.001). Tumors showed histopathological hallmarks of GBM and retained its glial identity verified by GFAP and vimentin immunoreaction. Immunosuppression of rats with cyclosporin was efficient in allowing the development of human glioblastoma cells in subcutaneous tissues. The model has demonstrated the maintenance of most of the histopathological characteristics of human glioblastoma in an heterotopic site and might by considered in research of molecular and proliferative pathways of malignant gliomas.


Ostapchenko V.G.,University of Western Ontario | Beraldo F.H.,University of Western Ontario | Guimaraes A.L.S.,University of Western Ontario | Guimaraes A.L.S.,State University of Montes Claros | And 6 more authors.
Journal of Neurochemistry | Year: 2013

Prion protein (PrPC), a glycosylphosphatidylinositol-anchored protein corrupted in prion diseases, has been shown recently to interact with group I metabotropic glutamate receptors (mGluRs). Moreover, both PrP C and mGluRs were proposed to function as putative receptors for β-amyloid in Alzheimer's disease. PrPC can be processed in neurons via α or β-cleavage to produce PrPC fragments that are neuroprotective or toxic, respectively. We found PrPC α-cleavage to be 2-3 times higher in the cortex of APPswe/PS1dE9 mice, a mouse model of Alzheimer's disease. A similar age-dependent increase was observed for PrPC β-cleavage. Moreover, we observed considerable age-dependent increase in cortical expression of mGluR1, but not mGluR5. Exposure of cortical neuronal cultures to β-amyloid oligomers upregulated mGluR1 and PrPC α-cleavage, while activation of group I mGluRs increased PrPC shedding from the membrane, likely due to increased levels of a disintegrin and metalloprotease10, a key disintegrin for PrP C shedding. Interestingly, a similar increase in a disintegrin and metalloprotease10 was detected in the cortex of 9-month-old APPswe/PS1dE9 animals. Our experiments reveal novel and complex processing of PrPC in connection with mGluR overexpression that seems to be triggered by β-amyloid peptides. © 2013 International Society for Neurochemistry.


Beraldo F.H.,University of Western Ontario | Soares I.N.,University of Western Ontario | Soares I.N.,Federal University of Minas Gerais | Goncalves D.F.,University of Western Ontario | And 25 more authors.
FASEB Journal | Year: 2013

Stress-inducible phosphoprotein 1 (STI1) is part of the chaperone machinery, but it also functions as an extracellular ligand for the prion protein. However, the physiological relevance of these STI1 activities in vivo is unknown. Here, we show that in the absence of embryonic STI1, several Hsp90 client proteins are decreased by 50%, although Hsp90 levels are unaffected. Mutant STI1 mice showed increased caspase-3 activation and 50% impairment in cellular proliferation. Moreover, placental disruption and lack of cellular viability were linked to embryonic death by E10.5 in STI1-mutant mice. Rescue of embryonic lethality in these mutants, by transgenic expression of the STI1 gene, supported a unique role for STI1 during embryonic development. The response of STI1 haploinsufficient mice to cellular stress seemed compromised, and mutant mice showed increased vulnerability to ischemic insult. At the cellular level, ischemia increased the secretion of STI1 from wild-type astrocytes by 3-fold, whereas STI1 haploinsufficient mice secreted half as much STI1. Interesting, extracellular STI1 prevented ischemia-mediated neuronal death in a prion proteindependent way. Our study reveals essential roles for intracellular and extracellular STI1 in cellular resilience.- Beraldo, F. H., Soares, I. N., Goncalves, D. F., Fan, J., Thomas, A. A., Santos, T. G., Mohammad, A. H., Roffe, M., Calder, M. D., Nikolova, S., Hajj, G. N., Guimaraes, A. N., Massensini, A. R., Welch, I., Betts, D. H., Gros, R., Drangova, M., Watson, A. J., Bartha, R., Prado, V. F., Martins, V. R., and Prado, M. A. M. Stress-inducible phosphoprotein 1 has unique cochaperone activity during development and regulates cellular response to ischemia via the prion protein. © FASEB.

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