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Neuroscience
 
Neuroscience Homepage  > Faculty List > Dubinsky
Janet Dubinsky, Ph.D.
Professor, Department of Neuroscience
dubin001@umn.edu                                                           

Neurodegeneration As a Result of Glutamate Toxicity.

Glutamate, the major excitatory neurotransmitter in the central nervous system, can be toxic when applied to neurons at high concentrations. Overstimulation of central glutamate receptors results in a slowly progressive neuronal death both in vitro and in vivo. This "excitotoxicity" is believed to contribute to the neurodegeneration connected with both acute and progressive neurological disorders such as trauma, stroke, epilepsy, Huntington's disease, and AIDS-related dementia. The laboratory's efforts are aimed at understanding the intracellular, physiological consequences of overstimulation of glutamate receptors.

We are studying intracellular ionic homeostasis and metabolic function in cultured central neurons. We employ protein chemistry, functional mitochondrial assays, molecular biology, microscope-based photometry and image processing, immunocytochemistry, biochemical and patch clamp electrophysiology techniques. We have shown that elevated intracellular calcium concentrations recover to normal levels but that hydrogen ion homeostasis does not recover following toxic glutamate exposure. We have demonstrated that oxygen mediates a component of delayed glutamate toxicity. Understanding the intermediate steps that lead to neuronal death will lead to improved strategies for interventions to prevent disease-related neurodegeneration.

We are interested in the role mitochondria play in both apoptotic and excitotoxic neurodegenerative processes.  A possible candidate contributor to neuronal demise is onset of the mitochondrial permeability transition, activated by elevated cytoplasmic calcium and/or oxidative events.  We have thoroughly characterized the permeability transition in CNS mitochondria and cultured neurons in response to calcium.  We have also delineated the conditions for mitochondrial Cytochrome c release in response to proapoptotic proteins and calcium.  Currently we are studying the differential susceptibility of striatal neurons in Huntington’s Disease to excitotoxicity.  Our hypothesis posits that differential mitochondrial susceptibility to the permeability transition may play a role. 

Selected Publications
Zacharoff L., Tkac I., Song Q., Tang C., Bolan P.J., Mangia S., Henry P.G., Li T. and Dubinsky J.M. (2011)
Cortical metabolites as biomarkers in the R6/2 model of Huntington's disease.
J. Neurosci. 30(24): 8057-60
Dubinsky JM. (2010)
Neuroscience education for prekindergarten-12 teachers.
J. Neurosci. 30(24): 8057-60
Dubinsky JM. (2009)
Heterogeneity of nervous system mitochondria: location, location, location!
Exp. Neurol. 218(2): 293-307
Weivoda S., Andersen J.D., Skogen A., Schlievert P.M., Fontana D., Schacker T., Tuite P., Dubinsky J.M. and Jemmerson R. (2008)
ELISA for human serum leucine-rich alpha-2-glycoprotein-1 employing cytochrome c as the capturing ligand.
J. Immunol. Methods 336(1): 22-29
Tkac I., Dubinsky J.M., Keene C.D., Gruetter R. and Low W.C. (2007)
Neurochemical changes in Huntington R6/2 mouse striatum detected by in vivo 1H NMR spectroscopy.
J. Neurochem. 100(5): 1397-406
MacNabb C., Schmitt L., Michlin M., Harris I., Thomas L., Chittendon D., Ebner T.J. and Dubinsky J.M. (2006)
Neuroscience in middle schools: a professional development and resource program that models inquiry-based strategies and engages teachers in classroom implementation.
CBE Life Sci. Educ. 5(2): 144-57
Jemmerson R., Dubinsky J.M. and Brustovetsky N. (2005)
Cytochrome C release from CNS mitochondria and potential for clinical intervention in apoptosis-mediated CNS diseases.
Antioxid. Redox. Signal. 7(9-10): 1158-72
Brustovetsky N., LaFrance R., Purl K.J., Brustovetsky T., Keene C.D., Low W.C. and Dubinsky J.M. (2005)
Age-dependent changes in the calcium sensitivity of striatal mitochondria in mouse models of Huntington's Disease.
J. Neurochem. 93(6): 1361-70
Dubinsky J.M., Brustovetsky N. and LaFrance R. (2004)
Protective roles of CNS mitochondria.
J. Bioenerg. Biomembr. 36(4): 299-302
Brustovetsky N., Brustovetsky T., Purl K.J., Capano M., Cromton M. and Dubinsky J.M. (2003)
Increased susceptibility of striatal mitochondria to calcium-induced permeability transition.
J. Neurosci. 23(12): 4858-67
Brustovetsky N., Dubinsky J.M., Antonsson B. and Jemmerson, R.
Two pathways for tBID-induced cytochrome c release from rat brain mitochondria: BAK- versus BAX-dependence.
J. Neurochem. 2003 84: 196-207
Brustovetsky N., Jemmerson R. and Dubinsky J.M.
Calcium-induced Cytochrome c release from rat brain mitochondria is altered by digitonin.
Neurosci. Lett. 332(2): 91-94
Brustovetsky N., Brustovetsky T., Jemmerson R. and Dubinsky J.M. (2002)
Calcium-induced cytochrome c release from CNS mitochondria is associated with the permeability transition and rupture of the outer membrane.
J. Neurochem. 80(2): 207-18
Lakkaraju A., Rahman Y.E. and Dubinsky J.M. (2002)
Low-density lipoprotein receptor-related protein mediates the endocytosis of anionic liposomes in neurons.
J. Biol. Chem. 277(17): 15085-92
Araki E., Forster C., Dubinsky J.M., Ross M.E. and Iadecola C. (2001)
Cyclooxygenase-2 inhibitor NS-398 protects neuronal Cultures from lipopolysaccaride-induced neurotoxicity.
Stroke 32(10): 2370-75.
 
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