Molecular mechanisms of neurodegenerative diseases.
The Palladino lab uses Drosophila as a model system to elucidate the cellular and molecular mechanisms of neurodegenerative diseases. Our lab has identified a large collection of novel neurodegenerative mutants using a powerful forward genetic approach. Characterization of these mutants will identify key proteins required for neural maintenance with age and a detailed understanding of the role of these gene products in human disease conditions. Our research program is directed toward three main goals: 1) discovering and characterizing novel pathways that cause neurodegenerative diseases, 2) understanding the physiological, cellular, and molecular dysfunction that causes neurodegeneration in vivo, and 3) using our animal system in pharmacological screens to identify neuroprotective compounds for the treatment of human neurodegenerative diseases.
We are currently focusing on elucidating the mechanism by which mutations affecting Na/K ATPase, triose phosphate isomerase (TPI), and mtATP6 function result in RDP (rapid-onset dystonia parkinsonism), glycolytic enzymopthy, and mitochondrial encephalaomyopathy, respectively. We are also funded to develop the methodology to use our neurodegenerative mutants in pharmacological screen to identify novel neuroprotectant compounds.
Liu, Z., Celotto, A,M., Romero, G., Wipf, P. and Palladino, M.J. Genetically encoded redox sensor identifies the role of ROS in degenerative and mitochondrial disease pathogenesis. Neurobiology of Disease, 45(1): 362-8, 2012.
Celotto, A,M., Liu, Z., VanDemark, A. P. and Palladino, M.J. A novel Drosophila SOD2 mutant demonstrates a role for mitochondrial ROS in neurodevelopment and disease. Brain and Behavior, 2(4): 423-34, 2012.
Celotto, A,M., Chiu, W.K., Van Voorhies, W. and Palladino, M.J. Modes of Metabolic Compensation during Mitochondrial Disease Using the Drosophila Model of ATP6 Dysfunction. PLoS ONE 6(10): e25823, 2011.
Hrizo, S.L. and Palladino, M.J. Hsp70 and Hsp90 mediate proteasomal degradation of TPIsugarkill that underlies pathogenesis. Neurobiology of Disease 40:676-683, 2010.
Ashmore LJ, SL Hrizo, SM Paul, W Van Voorhies, GJ Beitel and MJ Palladino. Novel mutations affecting the NA,K ATPase alpha model complex neurological diseases and implicate the sodium pump in increased longevity. Human Genetics 126: 431-447, 2009.
Celotto, A,M., Frank, A,C., McGrath, S.W., Fergestad, T.J., Van Voorhies, W.A., Buttle, K., Mannella, C.A., and Palladino, M.J. Mitochondrial encephalomyopathies in drosophila. Journal of Neuroscience 26(3): 810-820, 2006.
Palladino, M.J., JE Bower, R Kreber and Barry Ganetzky. Neural dysfunction and neurodegeneration in Drosophila Na+/K+ ATPase alpha subunit mutants. Journal of Neuroscience 23(4): 1276-1286, 2003.
Palladino, M.J., Keegan, L.P., O’Connell, M.A. and Reenan, R.A. A-to-I pre-mRNA editing in Drosophila is primarily involved in adult nervous system function and integrity. Cell 102(4): 437-449, 2000.