Through a long lasting collaboration between Dr. Luis Barbeito, we have made major progress towards l unraveling how oxidative stress involving peroxynitrite formation causes the death of motor neurons in Amyotrophic Lateral Sclerosis (ALS). We have proposed a novel mechanism to explain how Zn-deficient SOD may cause motor neuron disease and have together coauthored 12 papers on these subjects over the past 7 years. Most recently, we have found that astroglia can play a pathogenic role in motor neuron degeneration. It is well known that reactive astrocytes surround degenerating motor neurons in ALS patients as well as in transgenic mice and rats over-expressing ALS mutant SOD-1. We found that peroxynitrite triggers a long-lasting phenotypic transformation in astrocytes, which promotes apoptosis of motor neurons cultured on the monolayers by mechanisms dependent on nitric oxide (NO) and peroxynitrite formation. Preliminary data implicates astrocytic synthesis of nerve growth factor (NGF) and its precursor form proNGF in triggering motor neuron apoptosis through activation of the """"""""low affinity"""""""" NGF receptor p75NTR. We hypothesize that zinc-deficient SOD plus nitric oxide will activate astrocytes and contribute to the progression of motor neuron death through activating NGF/p75NTR signaling. To test this hypothesis, we propose to characterize whether zinc deficient SOD can make astrocytes reactive and induce NGF synthesis and secretion. The pro-apoptotic activity of the different NGF forms will be tested on cultured motor neurons and in vivo studies will be performed to analyze whether blockade of NGF/p75NTR pathway in G93A transgenic mice affect disease progression. These additional studies will provide important insight into astrocytes could contribute to the progressive death of motor neurons in ALS. Halting the progressive death of motor neurons in ALS could be of huge clinical significance.

Agency
National Institute of Health (NIH)
Institute
Fogarty International Center (FIC)
Type
Small Research Grants (R03)
Project #
5R03TW006482-03
Application #
6928535
Study Section
International and Cooperative Projects 1 Study Section (ICP)
Program Officer
Michels, Kathleen M
Project Start
2004-08-01
Project End
2006-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
3
Fiscal Year
2005
Total Cost
$40,320
Indirect Cost
Name
Oregon State University
Department
Type
Organized Research Units
DUNS #
053599908
City
Corvallis
State
OR
Country
United States
Zip Code
97339
Vargas, Marcelo R; Pehar, Mariana; Diaz-Amarilla, Pablo J et al. (2008) Transcriptional profile of primary astrocytes expressing ALS-linked mutant SOD1. J Neurosci Res 86:3515-25
Pehar, Mariana; Vargas, Marcelo R; Robinson, Kristine M et al. (2007) Mitochondrial superoxide production and nuclear factor erythroid 2-related factor 2 activation in p75 neurotrophin receptor-induced motor neuron apoptosis. J Neurosci 27:7777-85
Pehar, Mariana; Vargas, Marcelo R; Robinson, Kristine M et al. (2006) Peroxynitrite transforms nerve growth factor into an apoptotic factor for motor neurons. Free Radic Biol Med 41:1632-44
Robinson, Kristine M; Janes, Michael S; Pehar, Mariana et al. (2006) Selective fluorescent imaging of superoxide in vivo using ethidium-based probes. Proc Natl Acad Sci U S A 103:15038-43
Vargas, Marcelo R; Pehar, Mariana; Cassina, Patricia et al. (2006) Increased glutathione biosynthesis by Nrf2 activation in astrocytes prevents p75NTR-dependent motor neuron apoptosis. J Neurochem 97:687-96
Cassina, Patricia; Pehar, Mariana; Vargas, Marcelo R et al. (2005) Astrocyte activation by fibroblast growth factor-1 and motor neuron apoptosis: implications for amyotrophic lateral sclerosis. J Neurochem 93:38-46
Pehar, Mariana; Vargas, Marcelo R; Cassina, Patricia et al. (2005) Complexity of astrocyte-motor neuron interactions in amyotrophic lateral sclerosis. Neurodegener Dis 2:139-46
Vargas, Marcelo R; Pehar, Mariana; Cassina, Patricia et al. (2005) Fibroblast growth factor-1 induces heme oxygenase-1 via nuclear factor erythroid 2-related factor 2 (Nrf2) in spinal cord astrocytes: consequences for motor neuron survival. J Biol Chem 280:25571-9
Pehar, Mariana; Cassina, Patricia; Vargas, Marcelo R et al. (2004) Astrocytic production of nerve growth factor in motor neuron apoptosis: implications for amyotrophic lateral sclerosis. J Neurochem 89:464-73
Vargas, Marcelo R; Pehar, Mariana; Cassina, Patricia et al. (2004) Stimulation of nerve growth factor expression in astrocytes by peroxynitrite. In Vivo 18:269-74