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.
Representative Publications
- Menalled, L.B., Sison,
J.D., Wu, Y., Olivieri, M., Li., X.-J., Li, H., Zeitlin, S., and Chesselet,
M.-F. (2002) "Early motor dysfunction and striosomal distribution
of huntingtin microaggregates in Huntington's disease knock-in mice."
J. Neurosci., 22, 8266-8276.
- Dragatsis, I., and Zeitlin,
S. (2001) "A method for the generation of conditional gene repair
mutations in mice." Nucl Acids Res., 29, E10.
- Reiner, A., Del Mar, N.,
Meade, C.A., Yang, H., Dragatsis, I., Zeitlin, S., and Goldowitz,
D. (2001) "Neurons lacking huntingtin differentially colonize
brain and survive in chimeric mice." J. Neurosci., 21,
7608-7619.
- 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.
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