   
|
 |
| 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
|
 |
Jemmerson R, Dubinsky JM, Brustovetsky N.
Cytochrome C release from CNS mitochondria and potential for clinical intervention in apoptosis-mediated CNS diseases.
Antioxid Redox Signal. 2005 Sep-Oct;7(9-10):1158-72. Review. |
|
Brustovetsky N, LaFrance R, Purl KJ, Brustovetsky T, Keene CD, Low WC, Dubinsky JM.
Age-dependent changes in the calcium sensitivity of striatal mitochondria in mouse models of Huntington's Disease.
J Neurochem. 2005 Jun;93(6):1361-70. |
|
Dubinsky JM, Brustovetsky N, LaFrance R.
Protective roles of CNS mitochondria.
J Bioenerg Biomembr. 2004 Aug;36(4):299-302. Review.
|
|
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, Brustovetsky T, Purl KJ,
Capano M, Cromton M and Dubinsky JM
Increased susceptibility of striatal mitochondria to calcium-induced
permeability transition.
J. Neurosci. 2003 Jun 15;23(12):4858-67 |
|
Dubinsky, J.M., Levi, Y, Pinelis, V.
Monochlorobimane detection of sulfhydryls in cultured hippocampal
neurons.
Biol Membrane 2002 19:170-8 |
|
Brustovetsky N, Jemmerson R, Dubinsky JM.
Calcium-induced Cytochrome c release from rat brain mitochondria is
altered by digitonin.
Neurosci
Lett. 2002 332(2):91-4 |
|
Brustovetsky N, Brustovetsky T, Jemmerson
R, Dubinsky JM.
Calcium-induced cytochrome c release from CNS mitochondria is associated
with the permeability transition and rupture of the outer membrane.
J
Neurochem 2002 Jan;80(2):207-18 |
|
Lakkaraju A, Rahman YE, Dubinsky JM.
Low-density lipoprotein receptor-related protein mediates the endocytosis
of anionic liposomes in neurons.
J
Biol Chem 2002 Apr 26;277(17):15085-92 |
|
Araki E, Forster C, Dubinsky JM, Ross ME, Iadecola C.
Cyclooxygenase-2 inhibitor NS-398 protects neuronal Cultures from lipopolysaccaride-induced neurotoxicity.
Stroke. 2001 Oct;32(10):2370-5. |
|
