Cellular and Molecular Biology

Group Leader: Vilma R. Martins Dr. Vilma R. Martins

Prions, the agents of transmissible spongiform encephalopathies, require the expression of a cellular homologue (PrPc) to propagate disease. The last is converted into an abnormal insoluble form, PrPsc, which a possible gain of neurotoxic activity. The accumulation of the toxic insoluble PrPsc has been described to be the most probable event responsible for neuronal death in prion diseases. However, since clinical manifestations may occur either before or without characteristic PrPsc deposits, it has been suggested that neurotoxicity is unlikely to be the unique cause for the pathogenesis of such maladies.

In the last few years several biological functions of PrPc have been uncovered and the idea that PrPc loss-of-function may have a role in the pathogenesis of prion diseases is still controversial and subject of intense discussion.

PrPc is a cell surface GPI (glycosyl-phosphatidylinositol) anchored protein which is highly conserved among species and ubiquitously expressed but predominantly in the nervous system. Strong evidence for a neuroprotective PrPc function derives from our description of a putative PrPc p66 ligand (Martins et al, 1997), which was later identified as the Stress Inducible protein 1, STI-1 (Zanata et al., 2002). The interaction between PrPc and STI-1 prevented programmed cell death of undifferentiated post-mitotic retinal cells (Chiarini, 2002) and hippocampal neurons (Lopes et al., 2005) which requires activity of cAMP-dependent protein kinase (PKA) (Chiarine et al., 2002, Lopes et al., 2005). These proteins association also mediates neuronal differentiation through Erk pathway (Lopes et al., 2005).We also demonstrated that PrPc associates to two extracelular matrix proteins, Laminin (Granet et al., 2000 and Graner et al., 2000b) and vitronectin (Hajj et al., under evaluation) mediating neuronal differentiation.

We believe that PrPc loss-of-function may contribute at least in part for the etiopathology of prion diseases. Moreover, due to the pleiotropic functions of PrPc, alterations at this molecule can also be related to maladies other than prion diseases.

The Molecular & Cellular Biology group has been focuses in the role of cellular prion protein in cellular functions during development and in adult animals. In order to approach that we made available a laser scanning confocal microscopy facility and mesmerized techniques necessary for cell biology especially those related to the production of recombinant proteins and determination of sub-cellular localization of proteins in live cells. We also establish the measurements of Ca+2 signaling in live cells and experimental conditions to run FRET (Fluorescence Resonance Energy Transfer) experiments.

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