JEFFREY N. KELLER, Ph.D.

UK Department of Anatomy and Neurobiology

Faculty Research

JEFFREY N. KELLER, Ph.D.
Ph.D., University of Kentucky (1997)
Assistant Professor of Anatomy and Neurobiology

Research Interests: Role of the Proteasome in Neurodegeneration

The primary focus of my laboratory is to determine the role of the proteasome, and proteasome inhibition, in Alzheimer’s disease (AD), Huntington’s disease (HD), stroke, and normal aging. The proteasome is a large intracellular enzyme, that is present in all cells, that is responsible for the majority of overall protein degradation. In particular the proteasome is responsible for the degradation of oxidized and apoptotic proteins. We have demonstrated that the activity of the proteasome is inhibited in neurodegenerative disorders (AD,HD,stroke, aging), and may therefore be responsible for increases in protein oxidation and apoptosis in those conditions. Because very little is known about the expression of the proteasome and proteasome activity in the normal and diseased brain, and even less is known about the possible role of proteasome inhibition in neurodegeneration, our lab is trying to answer these important questions. Studies are conducted using chiefly molecular techniques in cellular, animal, and human tissue. A second objective of our laboratory is aimed at defining the genes which contribute to HD. We have identified a number of genes, some of which are novel previously unidentified genes, that are elevated in presymptomatic and symptomatic HD mice.

Representative Publications

Keller, J.N., M.S. Kindy, F.W. St. Clair, H.C. Yen, A. Germeyer, S.M. Steiner, A.J. Bruce-Keller, J.B. Hutchins, and M.P. Mattson. Mitochondrial MnSOD prevents neural apoptosis and reduces ischemic brain injury: Suppression of peroxynitrite production, lipid peroxidation, and mitochonidrial dysfunction. Journal of Neuroscience. 18:678-697, 1998.

Keller, J.N., Q. Guo, F.W. Holtsburg, A.J. Bruce-Keller, and M.P. Mattson. Increased sensitivity to mitochondrial toxin-induced apoptosis in neural cells expressing mutant presenilin-1 is linked to perturbed calcium homeostasis and enhanced oxyradical production. Journal of Neuroscience. 18: 4439-4450, 1998.

Keller, J.N., K.B. Hanni, and W.R. Markesbury. Inhibition of the multicatalytic proteasome in Alzheimer’s disease: Implications for oxidative stress. Journal of Neurochemistry. IN PRESS

Keller, J.N., K.B. Hanni, and W.R. Markesbury. Inhibition of the multicatalytic proteasome during aging: Implications for oxidative stress. Mech. Aging Dev. 113: 61-70, 2000.

Keller, J.N., F.F. Huang, and W.R. Markesbury. Decreased levels of proteasome activity and proteasome subunit expression during aging in rat spinal cord: Effects on neuronal survival. Neuroscience. 98: 149-156, 2000

Keller, J.N. F.F. Huang, E. Dimagaya, and W.F. Maragos. Dopamine induces proteasome inhibition. Free Radical Biological Medicine. IN PRESS.

Keller, J.N., F.F. Huang, H. Zhu, J. Yu, Y. Ho, and M.S. Kindy. Oxidative stress-associate impairment of proteasome activity during ischemia-reperfusion injury. Journal of Cerebral Blood flow Metabolism. 20: 1467-1473, 2000.

Keller, J.N. and Markesbury, W.R. Inhibition of the proetasome increases Poly-ADP ribosylaton: Implications for neuron death. Journal of Neuroscience Research. 61: 436-442, 2000.

Ding, Q. and Keller, J.N. Heat shock proteins and proteasome in oxidative stress. Journal of Neurochemistry. IN PRESS.

Ding, Q. and Keller, J.N. Proteasome and proteasome inhibition in the central nervous system. Free Radical Biological Medicine. IN PRESS.

e-mail: jnkell0@uky.edu
phone: (859)323-0042
fax: (859)323-5946
Laboratory homepage