Our approach is to use the simple and
manipulable model organism Drosophila
in order to approach the complex problem
of human neurodegenerative disease.
So these are the types of
diseases that I'm talking about.
Alzheimer's disease, other dementias, as
well as the polyglutamine repeat diseases,
of which Huntington's disease
is probably the best known.
So these diseases share the fact that they
have a similar type of general phenotype
which is late onset and progressive,
They also are associated with
Those can be in different
places of the cell, and
they're composed of different
proteins in the different diseases.
But the fact that they have these
commonalities suggest that there might
be some commonalities among
these different diseases.
For all of these situations, genes have
been associated with the diseases and
with the gene, the typical ideas
to model those in other systems so
one can learn about disease mechanisms.
And whereas mouse or cells in culture
had been the popular way to go,
we decided to try Drosophila, which
has pathways very conserved to humans.
And if we could generate a phenotype
in the flies that looks like the human
disease, we could then apply the powerful
genetics of the fly to the problem.
So this illustrates the class of diseased
gene that I'm going to be talking about
which are the human polyglutamine
repeat disease genes,
of which there about 9 in humans.
I'm going to focus on our studies using
the spinocerebellar ataxia type 3 protein,
the SCA-3 protein, ataxin-3 is also
known as Machado Joseph Disease,
although probably the best known of
these diseases is Huntington's disease.
So on the right illustrates the mutational
mechanism responsible for these disease
genes, so it shows the genes and in red
it highlights the polyglutamine repeat
that becomes expanded out in these disease
situations, so all of these proteins have
a normal polyglutamine repeat and
that becomes expanded for disease.
The longer the expansion, the earlier
the onset and more severe the disease.
So in addition to being interested in
how that protein confers a toxicity that
causes the disease on the left-hand side
shows some of the features of the disease,
including the regions that are most
affected in the different diseases.
So an interesting feature of these
diseases is that despite the fact that
the disease proteins tend to be widely
expressed, they cause disease in only
certain sub-regions of the brain and that
indicates that there may be some degree of
cell specificity that perhaps is conferred
by the normal host protein context.