STAFF
| LUIS BARBEITO M.D. | Professor |
| JOSE R. SOTELO-SILVEIRA Ph.D. | Associate Researcher |
| MARIANA PEHAR Msc. | Associate Researcher |
| MARCELO VARGAS MSc. | Graduate Student |
| RAQUEL CASTELLANOS M.D. | Graduate Student |
| LAURA LAFON Msc. | Technician |
| NATALIA GUELFI | Assistant Member |
| PATRICIA CASSINA | (Invited Researchers from the Facultad de Medicina, U. de la República) |
Overview
The major focus of the Department of Cellular and Molecular Neurobiology is the study of mechanisms involved in neuronal death, in particular those occurring in neurodegenerative diseases such as Amyotrophic Lateral Sclerosis and Alzheimer’s disease. Because the procise molecular processes leading to neurodegeneration are just beginning to be described, no adequate theory of the process exists. The development of modern methods of cell and molecular biology in the last decades has led to quite simplistic views of neurodegeneration, mainly focused on the phenomenologic descriptions of genes, proteins and organelles participating in neuronal death. In most neurodegenerative diseases, however, other cell types including glial and vascular cells are also involved. Rather, these cells interact with degenerating neurons by complex mechanisms. Our aim is to reconcile the cellular and molecular analysis of at least two types of interacting cells within the whole process of neurodegeneration. Some key question are, How do non-neuronal cells contibute to the pathogenesis of neurodegenerative diseases?; what is the role played by neuroinflammatory phenotype of glial cells?; which are the mediators involved?, what is the role of oxidative and nitrative stress in neurodegeneration? Our department seeks to answer these questions at several levels. Because the scarce national resources for research, our strategy is to perform collaborative research projects with national and international groups.
RESEARCH PROJECTS
-Neuronal-glial interactions in neurodegenerative diseases. P. Cassina, M. Pehar, M. Vargas and Luis Barbeito, in collaboration with: Patricia Cassina (Facultad de Medicina, UDELAR, Montevideo), Alvaro G. Estevez (Department of physiology and Biophysics, University of Alabama at Birmingham, and Joseph S. Beckman (Linus Pauling Institute, Oregon State University), Ricardo Maccioni, (Uiversidad de Chile), Hervé Chneiweiss (College de France, Paris), Jean Philippe Loeffler, (Universite Louis Pasteur, Strasbourg, France)
-Role of proNGF and high molecular forms of NGF on p75NTR-dependent neuronal apoptosis. M. Pehar, Marcelo Vargas, and Luis Barbeito, in collaboration with: Patricia Cassina (Facultad de Medicina, UDELAR, Montevideo) and Joseph S. Beckman (Linus Pauling Institute, Oregon State University), Pedro Alzari (Institut Pasteur, Paris), Frank Longo (University of North Caroline)
-FGF-1 signaling in Amyotrophic Lateral Sclerosis. M. Vargas , P. Cassina, M. Pehar, R. Castellanos and Luis Barbeito, in collaboration with Anthony Thompson (University of Alabama at Birmingham), and Joseph S. Beckman (Linus Pauling Institute, Oregon State University)
-Role of nitric oxide and peroxynitrite in motor neuron death. P. Cassina, M. Pehar, M. Vargas and L. Barbeito in collaboration with: Joe Beckman (LPI, Oregon State University), Alvaro G. Estevez (Department of physiology and Biophysics, University of Alabama at Birmingham, Rafael Radi (Facultad de Medicina, UDELAR, Montevideo).
PUBLICATIONS
Estevez AG.; Crow J.P; Sampson J, Barbeito L; Beckman JS. Zinc Deficient superoxide dismutase induces motor neuron apoptosis by an oxidative mechanisms. Science 296:2486-500,
Estevez AG., Spear N. Peluffo H., Kamaid A., Barbeito L, Beckman JS. Examining apoptosis in cultured cells after exposure to nitric oxide and peroxynitrite. Methods in Enzymology. 301:393-402.
Estévez AG, Sampson JB, Zhuang Y, Spear N, Richardson GJ, Crow JP, Tarpey MM, Barbeito L, Beckman JS. Liposome-delivered superoxide dismutase prevents nitric oxide-dependent motor neuron death induced by trophic factor withdrawal. Free Radic. Biol. Med. 28(3):437-446.
Cassina P, Peluffo H, Barbeito L. Adaptative responses of spinal astrocytes to oxidative stress. Progress Brain Research 132:413-425.
Beckman JS, Estévez AG, Crow J, Barbeito L. Superoxide dismutase and the death of motor neurons in ALS Trends in Neurosciences 24 : S15-20.
Maccioni RB, Munoz JP, Barbeito L . The molecular bases of Alzheimer's disease and other neurodegenerative disorders. Archives Medical Research 32:367-81.
Pehar, M, Martínez-Palma, L., Peluffo, H, Kamaid, A, Cassina, P. & Barbeito, L. Peroxynitrite-induced cytotoxicity in cultured astrocytes is associated with morphological changes and increased nitrotyrosine immunoreactivity. Neurotoxicity Res. 4 : 87-93.
Beckman JS, Estevez AG, Barbeito L, Crow JP. CCS knockout mice establish an alternative source of copper for SOD in ALS. Free Radic Biol Med. 33:1433-5.
Estevez AG, Kamaid A, Thompson JA, Cornwell TL, Radi R., Barbeito L, Beckman JS. Cyclic guanosine 5 monophosphate (GMP) prevents expression of neuronal nitric oxide synthase and apoptosis in motor neurons deprived of trophic factors. Neuroscience Letters 326:201-205.
Cassina P., Peluffo H, Pehar M, Martinez-Palma L. , Ressia A, Beckman J, Estevez A, Barbeito L. Peroxynitrite Triggers a Phenotypic Transformation in Spinal Cord Astrocytes that Induces Motor Neuron Apoptosis. Journal of Neuroscience Research 67:21-30.
Martinez-Palma L, Pehar M, Cassina P, Peluffo H, Castellanos R, Anesetti G, Beckman JS, Barbeito L. Involvement of nitric oxide on kainate-induced toxicity in oligodendrocyte precursors. Neurotoxicity Research 5: 385-394.
Roth AD, Leisewitz AV, Jung JE, Cassina P, Barbeito L, Inestrosa NC, Bronfman M. PPAR gamma activators induce growth arrest and process extension in B12 oligodendrocyte-like cells and terminal differentiation of cultured oligodendrocytes. Journal of Neuroscience Research 72:425-35.
Pehar M, Cassina P, Vargas M, Castellanos R, Viera L, Beckman JS, Estevez AG, Barbeito L.. Astrocytic production of NGF in motor neuron apoptosis. Journal of Neurochemistry
Peluffo H,, Shacka J.J., Bisig G., Ricart K., Martínez-Palma L., Pritsch O, Kamaid A, Eiserich J, Crow J, Barbeito L, Estévez A.G. Induction of Motor Neuron Apoptosis by Free 3-Nitro-L-tyrosine. Journal of Neurochemistry
Sotelo-Silveira JR, Calliari A, Cárdenas M, Koening E, Sotelo JR. Myosin Va and Kinesisn II motor ptoteins are concentrated in ribosomal domains (periaxoplasmic ribosomal plaques) of myelinated axons. J. Neurobiology.
Vargas M, Pehar M, Cassina P, Estévez AG, Beckman JS, Barbeito L.Stimulation of Nerve Growth Factor Expression in Astrocytes by Peroxynitrite In Vivo
Barbeito, L., Pehar, M., Cassina, P., Peluffo, H., Viera, L., Estévez, A.G. & Beckman, J.S. A role for astrocytes in motor neuron loss in Amyotrophic Lateral Sclerosis. Brain Res. Rev.
Sharif A, Renault F, Beuvon F, Castellanos R , Canton B , Barbeito L , Junier MP, Chneiweiss H. The expression of PEA-15 (Phosphoprotein Enriched in Astrocytes of 15 kDa) defines subpopulations of astrocytes and neurons throughout the adult mouse brain. Neuroscience
Patent Application: “Active or passive immunization against proapoptotic neurotrophins for the treatment and/or prevention of neurodegenerative diseases” Authors: Barbeito L, Pehar M, Cassina MP, Alzari P., Estevez A. Beckman JS. European Patent:
GRANTS
- Research Agreement “Peroxynitrite and motor neuron deat in ALS models” Linus Pauling Institute, Oregon State University
- “Astrocytes and Motor Neuron Apoptosis: Fogarty Grant-FIRCA/NIH RTW006482A--2003-2006. (in collaboration with Dr. J. Beckman (PI), Oregon State University).
- Regulación de la apoptosis de motoneuronas mediada por el receptor de neurotrofinas p75NTR. PDT-Dynacyt
- Participación del NGF en la muerte de motoneuronas. CSIC Universidad de la Republica. PI: P. Cassina.
- Relación entre las respuestas al estrés celular inducido por radicales libres y el peroxinitrito y los mecanismos de apoptosis en astrocitos normales y en los gliomas" ECOS-SUD (Francia-Uruguay). PI. LB