THESIS
2015
x, 57 pages : illustrations (some color) ; 30 cm
Abstract
Spinocerebellar Ataxia type 3 (SCA3) is an autosomal dominant polyglutamine disease
characterized by progressive neurodegeneration that leads to impaired motor coordination and
other symptoms. Exact disease mechanism of SCA3 is not fully understood and there are
currently no known therapy to prevent disease progression. SCA3 is solely caused by CAG
expansion of the gene ATXN3, which encodes a deubiquitinase with a unique
deubiquitinating mechanism. In a yeast-two hybrid screening, ATXN3 was found to interact
with PICK1, an adaptor protein with important functions in protein trafficking inside the
central nervous system and other organs. In addition, PICK1 was found to regulate the cell
loss caused by SCA3 through an unknown pathway in a Drosophila model. However, none of
these...[
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Spinocerebellar Ataxia type 3 (SCA3) is an autosomal dominant polyglutamine disease
characterized by progressive neurodegeneration that leads to impaired motor coordination and
other symptoms. Exact disease mechanism of SCA3 is not fully understood and there are
currently no known therapy to prevent disease progression. SCA3 is solely caused by CAG
expansion of the gene ATXN3, which encodes a deubiquitinase with a unique
deubiquitinating mechanism. In a yeast-two hybrid screening, ATXN3 was found to interact
with PICK1, an adaptor protein with important functions in protein trafficking inside the
central nervous system and other organs. In addition, PICK1 was found to regulate the cell
loss caused by SCA3 through an unknown pathway in a Drosophila model. However, none of
these studies were done mammalian systems and the mechanism is not clear.
In this study, PICK1 was verified to interact with ATXN3 in vitro, with both PICK1 and
ATXN3 bind to each other at multiple sites. Further mapping showed that BAR domain of
PICK1 binds specifically to the unstructured C-terminus of ATXN3, where the polyQ tract
resides. Such binding is specific to the BAR domain of PICK1 but not BAR domains of other
proteins identified with sequence homology. On top of the specific interaction, the BAR
domain of PICK1 recruits the C-terminal of ATXN3 from cytosol to form clusters. In addition,
two distinct forms of nuclear inclusion bodies were found in the SCA3 model mice brain,
along with additional brain areas containing nuclear inclusion bodies were identified. Further
studies on the interaction of these two proteins may reveal pathological mechanism of SCA3
and identify new drug targets.
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