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The role of celular prion protein in physiological and pathological processes

Grant number: 99/07124-8
Support type:Research Projects - Thematic Grants
Duration: March 01, 2000 - June 30, 2004
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Vilma Regina Martins
Grantee:Vilma Regina Martins
Home Institution: Instituto Ludwig de Pesquisa sobre o Câncer (ILPC). São Paulo , SP, Brazil

Abstract

Prions are an unconventional form of infectious agents composed of protein and involved in transmissible spongiform encephalopathies in human and animals. The infectious particle is composed by PrPsc which is an isoforrn of a normal cellularglycosyl-phosphatidylinositol (GPI) anchored protein, Prpc. The two proteins differ only in conformation, PrPc is composed of 40% (-helix structure while PrPsc has 60% (-sheet and 20% (-helix structure (Prusiner, 1991). PrPc is very conserved between the species what suggests an important cellular role for this protein (Prusiner, 1991), however its function is still unknown. PrPc is involved with mitogen-induced lymphocyte activation (Cashman et al.,1990) and regulation of intracellular calcium concentration in neuronal cells, suggesting that it could be involved with cellular differentiation. Mature PrPc is anchored to the outer surface of the plasma membrane by a GPI moiety, and conflicting data have shown that its internalization is mediated by clathrin-coated pits or by caveolae-like membranous domains. However, both pathways seem to require a third protein (a receptor or a prion binding protein) to make the connection between the GPI-anchored molecule and the internal face of the membrane (Harris et al.,1996). Our group has recently identified a specific receptor for cellular PrPc protein (Martins et al., 1997). We have recently observed that PrPc is able to bind larninin (Graner et al., submitted), the most important non collagenic component of the basal membrane, which has a pivotal role in proliferation, differentiation, migration and cellular death (Timp and Brown, 1994). Therefore, the study of PrPc interactions with its receptor and laminin in different experimental models would allow clarifying the physiological role of PrPc and its participation in other pathological process besides the spongiform encephalophaties. Model 1 - neuronal differentiation in vitro. - We will study the role of PrPc-laminin and PrPc-receptor binding and the participation of other known laminin ligand proteins such as integrins in neuronal cell differentiation (neuritogenesis) in primary culture from rat and mouse brains. Model 2 - neuronal tissue apoptosis (retina model): the retina is part of the central nervous system which has a very singular differentiation, a direct connection with the visual system in brain and expresses high amounts of PrPc protein. Therefore, a very interesting tissue to study the PrPc interactions and its physiological role. Model 3 - memory: PrPc is a neuronal membrane protein found in high concentrations in hippocampus. The evidences showing that neuroplasticity of neuronal membranes are responsible for memory formation suggest that PrPc would be involved in this process. Our goal is to analyze the role of hippocampal PrPc in emotional memory formation in rats and mice. We will verify the effects of intra-hippocampal infusions of PrPc ligands or antibodies in memory formation and moreover the behavior of PrPc knockout mice. Model 4 - epilepsy: it was observed that PrPc knockout mice (Collinge et al., 1993) had an alteration on GABA, receptor (y-aminobutiric acid type A) signaling which would be responsible for abnormal synchronization of electric events and epileptic activity. Using four different protocols for experimental epilepsy induction, we observed that PrPc knockout mice are much more sensitive than wild type animals (Walz et ai., 1999a). The relevance of PrPc and its ligands in this pathology will be evaluated in rats, normal mice and PrPc knockout mice. The higher epilepsy susceptibility in PrPc knockout mice suggests that lost of function of PrPc protein would be involved with pathological processes. The existence of hereditary forms of epilepsy led us to think about mutations on PrPc gene associated with the disease. Our idea is to sequence the PrPc gene in patients and their relatives with hereditary forms of epilepsy. Model 5 - cancer: The participation of laminin and its classical receptors in tumoral processes and metastasis are well known for a long time. Since PrPc binds to laminin and is expressed in all cell types, we want to analyze its role in the tumoral process. (AU)

Articles published in Pesquisa FAPESP Magazine about the research grant:
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Scientific publications (9)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
HAJJ, GLAUCIA N. M.; LOPES, MARILENE H.; MERCADANTE, ADRIANA F.; VEIGA, SILVIO S.; SILVEIRA, RAFAEL B. DA; SANTOS, TIAGO G.; RIBEIRO, KARINA C. B.; JULIANO, MARIA A.; JACCHIERI, SAUL G.; ZANATA, SILVIO M.; MARTINS, VILMA R. Cellular prion protein interaction with vitronectin supports axonal growth and is compensated by integrins. Journal of Cell Science, v. 120, n. 11, p. 1915-1926, May 2007.
THAIS‚ M.E.; CARQUEJA‚ C.L.; SANTOS‚ T.G.; SILVA‚ R.V.; STROEH‚ E.; MACHADO‚ R.S.; WAHLHEIM‚ D.O.; BIANCHIN‚ M.M.; SAKAMOTO‚ A.C.; BRENTANI‚ R.R.; OTHERS. Synaptosomal glutamate release and uptake in mice lacking the cellular prion protein. Brain Research, v. 1075, n. 1, p. 13-19, 2006.
LOBÃO-SOARES‚ B.; BIANCHIN‚ M.M.; LINHARES‚ M.N.; CARQUEJA‚ C.L.; TASCA‚ C.I.; SOUZA‚ M.; MARQUES‚ W.; BRENTANI‚ R.; MARTINS‚ V.R.; SAKAMOTO‚ A.C.; OTHERS. Normal brain mitochondrial respiration in adult mice lacking cellular prion protein. Neuroscience Letters, v. 375, n. 3, p. 203-206, 2005.
WALZ‚ R.; CASTRO‚ R.; LANDEMBERGER‚ MC; VELASCO‚ TR; TERRA-BUSTAMANTE‚ VC; BASTOS‚ AC; BIANCHIN‚ M.; WICHERT-ANA‚ L.; ARAUJO‚ D.; ALEXANDRE JR‚ V.; OTHERS. Cortical malformations are associated with a rare polymorphism of cellular prion protein. Neurology, v. 63, n. 3, p. 557-560, 2004.
COITINHO‚ A.S.; ROESLER‚ R.; MARTINS‚ V.R.; BRENTANI‚ R.R.; IZQUIERDO‚ I. Cellular prion protein ablation impairs behavior as a function of age. Neuroreport, v. 14, n. 10, p. 1375-1379, 2003.
WALZ‚ R.; CASTRO‚ R.; VELASCO‚ TR; ALEXANDRE JR‚ V.; LOPES‚ MH; LEITE‚ JP; SANTOS‚ AC; ASSIRATI JR‚ JA; WICHERT-ANA‚ L.; TERRA-BUSTAMANTE‚ VC; OTHERS. Surgical outcome in mesial temporal sclerosis correlates with prion protein gene variant. Neurology, v. 61, n. 9, p. 1204-1210, 2003.
CHIARINI, LUCIANA B.; FREITAS, ADRIANA R. O.; ZANATA, SILVIO M.; BRENTANI, RICARDO R.; MARTINS, VILMA R.; LINDEN, RAFAEL. Cellular prion protein transduces neuroprotective signals. EMBO Journal, v. 21, n. 13, p. 3317-3326, July 2002.
ZANATA, SILVIO M.; LOPES, MARILENE H.; MERCADANTE, ADRIANA F.; HAJJ, GLAUCIA N. M.; CHIARINI, LUCIANA B.; NOMIZO, REGINA; FREITAS, ADRIANA R. O.; CABRAL, ANA L. B.; LEE, KIL S.; JULIANO, MARIA A.; ET AL. Stress-inducible protein 1 is a cell surface ligand for cellular prion that triggers neuroprotection. EMBO Journal, v. 21, n. 13, p. 3307-3316, July 2002.
MARTINS‚ V.R.; LINDEN‚ R.; PRADO‚ M.A.M.; WALZ‚ R.; SAKAMOTO‚ A.C.; IZQUIERDO‚ I.; BRENTANI‚ R.R. Cellular prion protein: on the road for functions. FEBS Letters, v. 512, n. 1, p. 25-28, 2002.

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