Molecular Nneurogenetics, Spinocerebellar Ataxia, Major
Histocompatibility Complex Genetics
Dr. Orr's research program is focused on the molecular genetics of
mammalian development and neurodegenerative diseases. He and his
colleagues recently cloned the gene for an autosomal dominant form of
spinocerebellar ataxia (SCA 1). They showed that the disease is due to
expansion of an unstable trinucleotide repeat (CAG) within the SCA 1 gene,
which they have mapped to the short arm of human chromosome. They are
examining the role of the SCA 1 gene in normal CNS function and how this
mutation disrupts this function. The investigators will be working with
protein biochemists to characterize the normal and abnormal SCA 1 protein.
Studies of SCA 1 are related to Orr's broader interest in the molecular
genetics of development of the cerebellum, the region of the brain involved
in motor control. Researchers in his laboratory have cloned several genes
specifically expressed by Purkinje neurons. One of these, Pcp-2, is
expressed only by Purkinje neurons and retinal bipolar neurons.
Collaborative transgenic studies have been used to demonstrate that the 5Õ
upstream region of the Pcp-2 gene contains sequences capable of directing
(both spatially and temporally) expression to Purkinje cells. Most
recently, these sequences have been used to direct expression of SV40 T
antigen (TAG) to Purkinje cells in transgenic mice. Expression of TAG
results in the death and degeneration of Purkinje cells. These studies
with neuropathologist Brent Clark are continuing to determine the molecular
mechanism of SV40 TAG-induced cell death and to characterize the role of
Purkinje cells in the early stages of cerebellar development. Insights
from these basic biological investigations could be important for
developing genetic and other therapies for patients with neurodegenerative
diseases.
Orr has a long-standing interest in the genetics of the human major
histocompatibility complex (MHC). Researchers in his laboratory are
studying the expression of a member of the MHC class I gene family
designated HLA-G. This gene, unlike other members of the HLA gene complex,
is non-polymorphic and is expressed only in the extraembryonic tissue
during fetal development. Orr and his colleagues are interested in why the
fetus does not reject the tissue, since half of the MHC antigens come from
the father.. To determine whether HLA-G plays a role in this phenomenon,
they are exploring the molecular basis of HLA-G expression using hybrid
reporter gene constructs transfected into choriocarcinoma cells. HLA-G
expression is also being pursued in situ using transgenic mice.
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