Hope through Rehabilitation & Research
Weill Medical College, Cornell University
Department of Neurology and Neuroscience
The onset and severity of neurodegenerative diseases vary considerably because of genetic mutations, environmental factors and age, making development of treatments difficult. A relatively novel approach to neurodegeneration considers the genetic response of neuronal cells to chronic stress. Neurons maintain the same genome all throughout life and are not able to divide. They respond to stress by inducing a genetic adaptive response that activates the transcription of pro-survival genes. When the stress is prolonged, such as in aging or chronic exposure to pollutants, neurons may decide to undergo apoptosis or to maladapt to stress. The maladaptive phase leads to the activation of pathogenic mechanisms in the cell. The ultimate ability of cells to reprogram and respond to the environment is called epigenetics. The mechanisms that contribute to epigenetic regulation are non-coding RNAs (ncRNA), DNA methylation, chromatin remodeling via ATP-dependent processes, and covalent modifications on histone proteins. Accordingly, epigenetics, which literally means “above the genome”, determines which genes are expressed by the cells and sits at the fertile therapeutic interface between environmental changes and gene responses. An investigation of how to epigenetically modulate the activation of the adaptive response in injured neurons—and thereby enhance neuronal survival and maintain brain plasticity—is of extreme interest to this field. We have reported that transglutaminase 1 and transglutaminase 2, multifunctional, calcium-dependent enzymes, are highly induced in their message levels and activity after stroke and in in vitro models of neuronal oxidative stress and they contribute to the pathobiological events by modulating the transcription of genes important in the neuronal adaptive response to stress. I am currently working on a model in which transglutaminase is a critical mediator between pathological signaling and epigenetic modifications leading to gene repression.
2008-2012: Postdoctoral Fellow, Burke Medical Research Institute, Weill Medical College, Cornell University, White Plains, NY, USA.
2003-2008: Doctor of Philosophy in Life Science, The Open University, Milton Keynes, UK in collaboration with the Mario Negri Institute, Milan, Italy.
2003-2007: Specialist in Pharmacological Research, The Post-Graduate School of Pharmacology, Mario Negri Institute, Milan, Italy.
1997-2002: Master of Science in Medical Biotechnology at the School of Medicine, University of Torino, Torino, Italy (summa cum laude).
Peer reviewed publications
Basso, M.#, Berlin, J., Ko, B., Haskew-Layton, R., Sleiman, S.F., Antonyak, M.A., Cerione, R.A., Iismaa, S.E., Willis, D., and Ratan, R.R#. (2012) Transglutaminase inhibition protects against stress-induced neuronal death downstream of pathological Erk activation. (Journal of Neuroscience, 32(19), 6561-6569; # corresponding authorship). Featured article in This Week, The Journal of Neuroscience.
Sleiman, S.F., Berlin, J., Basso, M., Karuppagounder, S.S., Rohr, J., and Ratan, R.R. (2011) Histone Deacetylase Inhibitors and Mithramycin A Impact a Similar Neuroprotective Pathway at a Cross Road between Cancer and Neurodegeneration. Pharmaceuticals 4, 1183-1195.
Smirnova, N. A., Haskew-Layton R. E., Basso, M., Hushpulian D., Payappilly, J., Speer, R. E., Ahn, Y., Rakhman, I., Cole P. A., Ratan, R. R., and Gazaryan, I. G. (2011) Development of Neh2-luciferase reporter and its application for high throughput screening and real-time monitoring of Nrf2 activators. Chem Biol. 18(6):752-65.
Sleiman, S.F., Langley, B., Basso, M., Xia L., Payappilly, JB, Berlin, J., Kharel, MK, Hengchang Guo, H., Marsh, J.L., Thompson, L.M., Mahishi, L., Ahuja, P., MacLellan, W.R., Geschwind, D., Coppola, G., Rohr, J., and Ratan, R.R. (2011) Mithramycin is a gene selective Sp1 inhibitor that identifies a biological intersection between cancer and neurodegeneration. J Neurosci. 31(18):6858-6870.
McConoughey, S. J*., Basso, M.*#, Niatsetskaya, Z. V., Sleiman, S. F., Smirnova, N. A., Langley, B. C., Mahishi, L., Cooper, A. J., Antonyak, M. A., Cerione, R. A., Li, B., Starkov, A., Chaturvedi, R. K., Beal, M. F., Coppola, G., Geschwind, D. H., Ryu, H., Xia, L., Iismaa, S. E., Pallos, J., Pasternack, R., Hils, M., Fan, J., Raymond, L. A., Marsh, J. L., Thompson, L. M., and Ratan, R. R#. (2010). Inhibition of transglutaminase 2 mitigates transcriptional dysregulation in models of Huntington disease. EMBO Mol Med 2(9), 349-70 (* Equal authorship; # corresponding authorship). Closeup by Kazemi-Esfarjani and La Spada EMBO Mol Med 2, 335–337.
Sahawneh, M. A., Ricart, K. C., Roberts, B. R., Bomben, V. C., Basso, M., Ye, Y., Sahawneh, J., Franco, M. C., Beckman, J. S., and Estevez, A. G. (2010). Cu,Zn-superoxide dismutase increases toxicity of mutant and zinc-deficient superoxide dismutase by enhancing protein stability. J Biol Chem 285(44), 33885-97.
Smirnova, N. A., Rakhman, I., Moroz, N., Basso, M., Payappilly, J., Kazakov, S., Hernandez-Guzman, F., Gaisina, I. N., Kozikowski, A. P., Ratan, R. R., and Gazaryan, I. G. (2010). Utilization of an in vivo reporter for high throughput identification of branched small molecule regulators of hypoxic adaptation. Chem Biol 17(4), 380-91.
Niatsetskaya, Z., Basso, M., Speer, R. E., McConoughey, S. J., Coppola, G., Ma, T. C., and Ratan, R. R. (2010). HIF prolyl hydroxylase inhibitors prevent neuronal death induced by mitochondrial toxins: therapeutic implications for Huntington's disease and Alzheimer's disease. Antioxid Redox Signal 12(4), 435-43.
Basso, M., Samengo, G., Nardo, G., Massignan, T., D'Alessandro, G., Tartari, S., Cantoni, L., Marino, M., Cheroni, C., De Biasi, S., Giordana, M. T., Strong, M. J., Estevez, A. G., Salmona, M., Bendotti, C., and Bonetto, V. (2009). Characterization of detergent-insoluble proteins in ALS indicates a causal link between nitrative stress and aggregation in pathogenesis. PLoS One 4(12), e8130.
Nardo, G., Pozzi, S., Mantovani, S., Garbelli, S., Marinou, K., Basso, M., Mora, G., Bendotti, C., and Bonetto, V. (2009). Nitroproteomics of peripheral blood mononuclear cells from patients and a rat model of ALS. Antioxid Redox Signal 11(7), 1559-67.
Massignan, T., Casoni, F., Basso, M., Stefanazzi, P., Biasini, E., Tortarolo, M., Salmona, M., Gianazza, E., Bendotti, C., and Bonetto, V. (2007). Proteomic analysis of spinal cord of presymptomatic amyotrophic lateral sclerosis G93A SOD1 mouse. Biochem Biophys Res Commun 353(3), 719-25.
Ghezzi, P., Casagrande, S., Massignan, T., Basso, M., Bellacchio, E., Mollica, L., Biasini, E., Tonelli, R., Eberini, I., Gianazza, E., Dai, W. W., Fratelli, M., Salmona, M., Sherry, B., and Bonetto, V. (2006). Redox regulation of cyclophilin A by glutathionylation. Proteomics 6(3), 817-25.
Basso, M., Massignan, T., Samengo, G., Cheroni, C., De Biasi, S., Salmona, M., Bendotti, C., and Bonetto, V. (2006). Insoluble mutant SOD1 is partly oligoubiquitinated in amyotrophic lateral sclerosis mice. J Biol Chem 281(44), 33325-35.
Casoni, F., Basso, M., Massignan, T., Gianazza, E., Cheroni, C., Salmona, M., Bendotti, C., and Bonetto, V. (2005). Protein nitration in a mouse model of familial amyotrophic lateral sclerosis: possible multifunctional role in the pathogenesis. J Biol Chem 280(16), 16295-304.
Basso, M., Giraudo, S., Corpillo, D., Bergamasco, B., Lopiano, L., and Fasano, M. (2004). Proteome analysis of human substantia nigra in Parkinson's disease. Proteomics 4(12), 3943-52.
Corpillo, D., Gardini, G., Vaira, A. M., Basso, M., Aime, S., Accotto, G. P., and Fasano, M. (2004). Proteomics as a tool to improve investigation of substantial equivalence in genetically modified organisms: the case of a virus-resistant tomato. Proteomics 4(1), 193-200.
Basso, M., Giraudo, S., Lopiano, L., Bergamasco, B., Bosticco, E., Cinquepalmi, A., and Fasano, M. (2003). Proteome analysis of mesencephalic tissues: evidence for Parkinson's disease. Neurol Sci 24(3), 155-6.
Book Chapters or Reviews
Basso, M. Targeting transcriptional dysregulation in Huntington’s disease: description of therapeutic approaches. Chapter in the book "Huntington's Disease - Core Concepts and Current Advances" edited by Nagehan Ersoy Tunali, ISBN 978-953-307-953-0, InTech, February 2, 2012.
Sleiman, S. F.*, Basso, M.*, Mahishi, L., Kozikowski, A. P., Donohoe, M. E., Langley, B., and Ratan, R. R. (2009). Putting the 'HAT' back on survival signalling: the promises and challenges of HDAC inhibition in the treatment of neurological conditions. Expert Opin Investig Drugs 18(5), 573-84.
Instructor in Dr. Rajiv R. Ratan’s laboratory
Ongoing Research Support
P01 AG14930-10 (PI: Gibson/Group Leader: Ratan) 05/01/2010 – 04/30/2015
Mitochondrial Dysfunction in Neurogeneration of Aging
Modulation of genes involved in mitochondrial adaptation (Project 1)
Role: Research Scientist
The major goals of this project are to define the role of transglutaminase as a selective corepressor.
Nuclear transglutaminases and transcriptional modulation
Mitochondrial dysfunction is a common, enduring feature of aging and neurodegeneration. Mitochondria have essential functions for synaptically active neurons via their ability to provide needed energy, buffer calcium and modulate cell signaling via the appropriate production of reactive oxygen species. Disruption of these essential functions occurs as a result of toxin-induced damage to mitochondrial electron transport complexes, oxidative damage to proteins, and/or via inherited mutations in proteins that lead to loss of function or gain of function related mitochondrial damage. An area of emerging interest in the field of mitochondrial therapeutics is mitochondrial homeostasis. Nuclear adaptation to mitochondrial dysfunction is essential as only subsets of proteins are encoded in the mitochondrial genome. In preliminary studies, we demonstrate that pharmacological or molecular suppression of transglutaminase 2 (TGase) leads to the transcriptional upregulation of PGC 1α and cytochrome C, genes involved in mitochondrial homeostasis. In this context, TGase is localized to one of these promoters under steady state conditions but polyQ-huntingtin increases its localization to this promoter. Indeed, TGase inhibition results in a normalization of nearly 40% of the genes repressed in a culture model of HD. This normalization is associated with induction of mitochondrial genes and protection from mitochondrial toxin-induced death in striatal neurons, a fly model of HD, and in myoblasts from humans afflicted with HD. The global hypothesis of this Project is that Transglutaminase is a selective corepressor that exacerbates transcriptional dysregulation in HD and AD; TGase induced transcriptional dysregulation nullifies metabolic and antioxidant adaptation to mitochondrial dysfunction leading first to synaptic dysfunction and then cell death. We are exploring the mechanisms by which transglutaminases modulates transcription through two major hypotheses.
Hypothesis #1: TGase modifies histones leading to transcriptional silencing of genes essential for adaptation to mitochondrial dysfunction; these modifications are increased in AD and HD.
Hypothesis # 2 TGase can act via nuclear and extranuclear routes to enhance susceptibility to cell death in cellular models of AD or HD.