Marcelo Vargas, PhD
2006 Ph.D., Universidad de la República-Uruguay
Office: BSB 319A
Role of oxidative stress and mitochondrial dysfunction in neurodegeneration
My current research focuses on the development of new therapeutic strategies using mechanistic insights drawn from understanding astrocyte-motor neuron interaction in amyotrophic lateral sclerosis (ALS). ALS or Lou Gehrig's disease accounts for about 1 in 500 to 1 in 1,000 adult deaths in the United States and is caused by the progressive degeneration of motor neurons in the spinal cord, brain stem, and motor cortex. Motor neuron death leads to muscle weakness and paralysis causing death in one to five years from the time of symptoms onset. Most ALS cases are sporadic (SALS) and exposure to yet unidentified environmental toxicants might be responsible for SALS. About 5-10% of the cases are inherited (familial ALS, FALS) but FALS and SALS are phenotypically indistinguishable, and a significant share of our understanding come from the study of rodent models over-expressing ALS-linked mutant human superoxide dismutase 1 (hSOD1). Primary astrocytes isolated from mutant hSOD1 over-expressing mice induce motor neuron death in co-culture, and it has been demonstrated that astrocytes differentiated from spinal cord autopsy-derived neuronal progenitor cells from FALS and SALS patients are also toxic for motor neurons in co-culture. Since mitochondrial dysfunction has been linked to ALS and the toxicity of ALS-astrocytes, we seek to better define the role of mitochondrial dysfunction in motor neuron degeneration and investigate different strategies to modulate mitochondrial function in astrocytes as a potential therapeutic strategy for ALS. In this context, the two main areas of research in the lab are: i) to explore the role of antioxidant defenses in ALS using knockout mice for the glutamate-cysteine ligase modifier subunit (GCLM-/-) and ii) to investigate the role of NAD-dependent signaling in mitochondrial function in models of ALS.
Recent Publications | Additional Publications
- Harlan, B. A., Pehar, M., Sharma, D. R., Beeson, G., Beeson, C. C., and Vargas, M. R. (2016) Enhancing NAD+ Salvage Pathway Reverts the Toxicity of Primary Astrocytes Expressing Amyotrophic Lateral Sclerosis-linked Mutant Superoxide Dismutase 1 (SOD1). The Journal of biological chemistry 291, 10836-10846
- Diaz-Amarilla, P., Miquel, E., Trostchansky, A., Trias, E., Ferreira, A. M., Freeman, B. A., Cassina, P., Barbeito, L., Vargas, M. R., and Rubbo, H. (2016) Electrophilic nitro-fatty acids prevent astrocyte-mediated toxicity to motor neurons in a cell model of familial amyotrophic lateral sclerosis via nuclear factor erythroid 2-related factor activation. Free radical biology & medicine 95, 112-120
- Pehar, M., Ball, L. E., Sharma, D. R., Harlan, B. A., Comte-Walters, S., Neely, B. A., and Vargas, M. R. (2016) Changes in Protein Expression and Lysine Acetylation Induced by Decreased Glutathione Levels in Astrocytes. Molecular & cellular proteomics : MCP 15, 493-505
- Pehar, M., Beeson, G., Beeson, C. C., Johnson, J. A., and Vargas, M. R. (2014) Mitochondria-Targeted Catalase Reverts the Neurotoxicity of hSOD1G93A Astrocytes without Extending the Survival of ALS-Linked Mutant hSOD1 Mice. PloS one 9, e103438
- Vargas, M. R., Burton, N. C., Kutzke, J., Gan, L., Johnson, D. A., Schafer, M., Werner, S., and Johnson, J. A. (2013) Absence of Nrf2 or its selective overexpression in neurons and muscle does not affect survival in ALS-linked mutant hSOD1 mouse models. PloS one 8, e56625
- Viera, L., Radmilovich, M., Vargas, M. R., Dennys, C. N., Wilson, L., Barnes, S., Franco, M. C., Beckman, J. S., and Estevez, A. G. (2013) Temporal patterns of tyrosine nitration in embryo heart development. Free radical biology & medicine 55, 101-108
- Gan, L., Vargas, M. R., Johnson, D. A., and Johnson, J. A. (2012) Astrocyte-specific overexpression of Nrf2 delays motor pathology and synuclein aggregation throughout the CNS in the alpha-synuclein mutant (A53T) mouse model. The Journal of neuroscience : the official journal of the Society for Neuroscience 32, 17775-17787
- 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.
- Vargas, M. R. & Johnson, J. A. (2010) Astrogliosis in amyotrophic lateral sclerosis: role and therapeutic potential of astrocytes. Neurotherapeutics. 7:471-481.
- 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.
- 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.
- Vargas, M.R. & Johnson, J.A. (2009) The Nrf2-ARE ctyoprotective pathway in astrocytes. Expert. Rev. Mol. Med. 11:e17.
- 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.
- 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.
- 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.