Our research interests center on two pediatric neurodegenerative diseases, Spinal Muscular Atrophy (SMA) and Aromatic L-Amino Acid (AADC) Deficiency. SMA is a relatively common (carrier frequency of ~1 in 40) neuromuscular disorder caused by a deficiency of the SMN protein that results in spinal motor neuron degeneration. AADC deficiency is a multi-symptomatic disease caused by the inability to synthesize normal levels of the neurotransmitters, serotonin and dopamine. There is no effective cure for either disease. Available treatments are palliative at best.
We use model mice to investigate the molecular and cellular basis of neurodegeneration in the two diseases. Current projects utilize a combination of genetics, cell biology and functional assays to determine 1) the cellular site(s) of action of the SMN protein, 2) novel pathways linking protein deficiency in the two diseases to neurodegeneration and 3) the developmental requirements of AADC and SMN in health and disease. It is expected that the results of these experiments will be instrumental in the design and implementation of safe and effective treatments for the disorders. We are also interested in exploring the role of the SMN protein in other neurodegenerative disorders. Establishing a link between SMN and these disorders is likely to shed light on more general mechanisms involved in the susceptibility and degeneration of neurons subjected to deficiencies in ubiquitously expressed proteins. http://www.cumc.columbia.edu/news/in-vivo/vol4_3_july-august_05/index.html
• Kariya, S., Jacquier, A., Re, D., Nelson, K., Przedborski, S. and Monani, U.R.
(2012) Mutant superoxide dismutase 1 (SOD-1), a cause of familial amyotrophic lateral sclerosis, disrupts the recruitment of SMN, the spinal muscular atrophy protein to nuclear Cajal bodies. Hum. Mol. Genet.
• Lee, J-H., Awano, T., Park, G-H. and Monani, U.R.
(2012) Limited phenotypic effects of selectively augmenting the SMN protein in the neurons of a mouse model of severe spinal muscular atrophy. PLoS One
• Lutz, C.M., Kariya, S., Patruni, S., Osborne, M.A., Liu, D., Henderson, C.E., Li, D.K., Pellizzoni, L., Rojas, J., Valenzuela, D.M., Murphy, A.J., Winberg, M.L. and Monani, U.R.
(2011) Post-symptomatic restoration of SMN rescues the disease phenotype in a mouse model of severe spinal muscular atrophy. J. Clin. Invest.
• Park, G-H., Maeno-Hikichi, Y., Awano, T., Landmesser, L.T. and Monani, U.R.
. (2010) Reduced SMN protein in motor neuronal progenitors functions cell autonomously to cause spinal muscular atrophy in model mice expressing the human centromeric (SMN2) gene. J. Neurosci.
30, 12005 – 12019.
• Park, G-H., Kariya, S. and Monani, U.R.
(2010) Spinal muscular atrophy: new and emerging insights from model mice. Curr. Neurol. Neurosci. Rep.
• Kariya, S., Mauricio, R., Dai, Y. and Monani, U.R.
(2009) The neuroprotective factor Wld(s) fails to mitigate distal axonal and neuromuscular junction (NMJ) defects in mouse models of spinal muscular atrophy. Neurosci Lett.
• Kariya, S., Park, G-H., Maeno-Hikichi, Y., Leykekhman, O., Lutz, C., Arkovitz, M., Landmesser, L.T. and Monani, U.R.
(2008) Reduced SMN protein impairs maturation of the neuromuscular junctions in mouse models of spinal muscular atrophy. Hum. Mol. Genet.
• Gavrilina, T. O., McGovern, V. L., Workman, E., Crawford, T. O., Gogliotti, R. G., DiDonato, C. J., Monani, U.R.
, Morris, G. E., and Burghes, A. H. (2008). Neuronal SMN expression corrects spinal muscular atrophy in severe SMA mice while muscle-specific SMN expression has no phenotypic effect. Hum. Mol. Genet.
• Monani, U.R.
(2005) Spinal muscular atrophy: A deficiency of a ubiquitous protein; a disease of the motor neurons. Neuron
• McWhorter, M.L., Monani, U.R.
, Burghes, A.H.M. and Beattie, C.E. (2003) Knockdown of the survival motor neuron (Smn) protein in zebrafish causes defects in motor axon outgrowth and pathfinding. J. Cell Biol.
• Monani, U.R.
, Pastore, M.P., Gavrilina, T.O., Jablonka, S., Le, T.T., Andreassi, C., DiCocco, J.M., Lorson, C., Androphy, E.J., Sendtner, M., Podell, M. and Burghes, A.H.M. (2003) A transgene carrying an A2G missense mutation in the SMN gene modulates phenotypic severity in mice with severe spinal muscular atrophy. J. Cell Biol.