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Human neurodegenerative disease: insights from Drosophila genetics

Published on September 29, 2008 Reviewed on May 31, 2018   56 min

A selection of talks on Neuroscience

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0:00
Our approach is to use the simple and manipulable model organism Drosophila in order to approach the complex problem of human neurodegenerative disease.
0:12
So these are the types of diseases that I'm talking about. Parkinson's disease, 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, neurodegenerative disease. They also are associated with pathological inclusions. 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.
1:17
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.
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Human neurodegenerative disease: insights from Drosophila genetics

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