University of Virginia Health System

Assistant Professor of Neuroscience
Ph.D., 1985, Columbia University

Mechanisms of Huntington's Disease Pathogenesis

My laboratory is interested in understanding the pathogenetic mechanism of Huntington's disease (HD). HD is a dominantly inherited neurodegenerative disorder that affects about 1 in 10,000 people in the United States. In the most common form of the disease, onset occurs between the ages of 30 and 50 with symptoms that include involuntary movement (chorea), cognitive deficits, and dementia. There is no known effective therapy and disease progression over a 10-20 year period ends inevitably in death. The mutation causing HD is an expansion of CAG triplets located near the beginning of the coding region of the IT15 gene. The CAG triplets encode a stretch of polyglutamine that confers a new deleterious function on huntingtin, the protein encoded by the HD gene. Using the mouse as a model system, we are studying the consequences of expressing mutant forms of huntingtin and inactivating HD gene expression in selected tissues at different developmental times. Recently, we have developed conditionally mutant mice that have lost huntingtin expression in the forebrain. These mice exhibit a progressive neurodegenerative phenotype that resembles what is observed in mouse models expressing the mutant form of huntingtin. We are currently investigating the possibility that the HD mutation may also act in a dominant negative fashion, resulting in the loss of huntingtin's normal neuroprotective functions.

UVa's Huntington's Disease Journal Club brings together faculty and students to discuss research and current topics in the HD field.  Click here for a link to the Huntington's Disease Journal Club.

Representative Publications

• Dragatsis, I., Levine, M., and Zeitlin, S. (2000) Inactivation of Hdh in the brain and testis results in progressive neurodegeneration and sterility. Nat. Genet. 26: 300-306.
  

• Dragatsis, I. and Zeitlin, S. (2000) CaMKIIa-cre transgene expression and recombination patterns in the mouse brain. Genesis 26: 133-135.
  

• Dragatsis, I., Dietrich, P., and Zeitlin, S. (2000) Expression of the Huntingtin-associate protein 1 gene (Hap1) in the developing and adult mouse. Neurosci. Lett. 282: 37-40.
  

• Menalled, L., Zanjani, H., MacKenzie, L., Koppel, A., Carpenter, E., Zeitlin, S., and Chesselet, M.-F. (2000) Decrease in striatal enkephalin mRNA in mouse models of Huntington's disease. Exp. Neurol. 162: 328-342.
  

• Levine, M.S., Klapstein, G.J., Koppel, A., Gruen, E., Cepeda, C., Vargas, M.E., Jokel, E.S., Carpenter, E.M., Zanjani, H., Hurst, R.S., Efstratiadis, A., Zeitlin, S., and Chesselet, M.-F. (1999) Enhanced sensitivity to N-methyl-D-aspartate receptor activation in transgenic and knockin mouse models of Huntington's disease. J. Neurosci. Res. 58: 515-532.
  

• Dragatsis, I., Efstratiadis, A., and Zeitlin, S. (1998) Mouse mutant embryos lacking huntingtin are rescued from lethality by wild-type extraembryonic tissues. Development 125: 1529-1539.
  

• Zeitlin, S., Liu, J.-P., Chapman, D.L., Papaioannou, V.E., and Efstratiadis, A. (1995) Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington's disease gene homologue. Nat. Genet. 11: 155-163.