Marcelo Vargas, PhD
2006 Ph.D., Universidad de la República-Uruguay
Office: BSB 319A
Role of oxidative stress and mitochondrial dysfunction in neurodegeneration
Amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig's disease, is the most common adult motor neuron disease. The disease's primary hallmark is the selective dysfunction and death of the neurons in the motor pathways. Among the familial cases, approximately 20% are caused by dominantly inherited mutations in the Cu, Zn superoxide dismutase (SOD1). Several hypotheses, including oxidative stress induced by SOD1 aberrant catalysis, glutamate excitotoxicity, formation of high molecular weight aggregates, and mitochondrial dysfunction have been proposed to explain the toxic effect of mutant SOD1. Mitochondrial vacuolar pathology has been observed in end-stage hSOD1G37R and both high and low copy hSOD1G93A. Remarkably, although they develop motor neuron degeneration, mitochondrial pathology has not been found in any of the models that overexpress mutants without dismutase activity, like hSOD1H46R/H48Q. Our ongoing experiments show that decreased GSH content accelerates the disease and aggravates the mitochondria pathology in hSOD1G93A but not in hSOD1H46R/H48Q mice. On the aforementioned context, the specific aims of the proposal are: Aim 1-To evaluate the effect of reduced GSH levels on the onset and progression of the disease in hSOD1G93A, hSOD1H46R/H48Q and hSOD1WTmice. Aim 2-To determine the role of hSOD1-induced mitochondrial dysfunction in the toxicity of astrocytes expressing ALS-linked mutant SOD1s toward co-cultured motor neurons. Aim 3-To evaluate the effect of increased mitochondrial peroxide detoxification in the onset and progression of disease in hSOD1G93A and hSOD1H46R/H48Q mice.
Recent Publications | Additional Publications
1. Vargas, M. R., Johnson, D. A. & Johnson, J. A. (2011) Decreased glutathione accelerates neurological deficit and mitochondrial pathology in familial ALS-linked hSOD1G93A mice model. Neurobiol. Dis. 43:543-551.
2. Vargas, M. R. & Johnson, J. A. (2010) Astrogliosis in amyotrophic lateral sclerosis: role and therapeutic potential of astrocytes. Neurotherapeutics. 7:471-481.
3. Calkins, M. J., Vargas, M. R., Johnson, D. A. & Johnson, J. A. (2010) Astrocytespecific overexpression of Nrf2 protects striatal neurons from mitochondrial complex II inhibition. Toxicol. Sci. 115:557-568.
4. Barbeito, A. G., Martinez-Palma, L., Vargas, M. R., Pehar, M., Mañay, N., Beckman, J. S. Barbeito, L.& Cassina, P. (2010) Lead exposure stimulates VEGF expression in the spinal cord and extends survival in a mouse model of ALS. Neurobiol Dis. 37:574-580.
5. Vargas, M.R. & Johnson, J.A. (2009) The Nrf2-ARE ctyoprotective pathway in astrocytes. Expert. Rev. Mol. Med. 11:e17.
6. Calkins, M.J. Johnson, D.A., Townsend, J.A., Vargas, M.R., Dowell, J.A, Williamson, T.P., Kraft, A.D.,Lee, J.M, Li,J. & Johnson, J.A. (2009) The Nrf2/ARE pathway as a potential therapeutic target in neurodegenerative disease. Antioxid. Redox. Signal. 11:497-509.
7. Chen, P.C., Vargas, M.R., Pani, A.K., Smeyne, R.J., Johnson, D.A., Kan, Y.W. & Johnson, J.A. (2009) Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson's disease: Critical role for the astrocyte. Proc Natl. Acad. Sci. U.S.A. 1096:2933-2938.
8. Vargas, M.R., Johson, D.A., Sirkis, D.W., Messing, A. & Johson, J.A. (2008) Nrf2 activation in astrocytes protects against neurodegeneration in mouse models of familial amyotrophic lateral scherosis. J. Neurosci. 28:13574-13581.