Research Frontiers

Dr. Ron Kopito and Dr. Brigit Riley

Autophagy research in the Kopito Lab

Dr. Riley looks specifically at the role of the microtubules in triggering autophagy. Microtubules may assist the fusion of the vesicles and the lysosome to form the active autolysosome that carries out autophagy. Dr. Riley believes that this is the link between microtubules and autophagy. In fact, experiments have shown that mutating the microtubules to disrupt their structure interferes with autophagy.

Researchers do not know for sure that autophagy is completely protective for the cell. It is possible that aggresomes activate autophagy, but instead of only targeting the aggresomes, autophagy targets everything in the cell. In this case, autophagy would be blindly degrading essential proteins and organelles along with the aggresomes, thus harming the cell. Autophagy would be a good temporary solution, but bad for the cell in the long run.

Dr. Riley also suggests that when aggresomes get degraded during autophagy, the resulting fragments of altered huntingtin protein act as the toxic molecule that harms the cell. Another possibility is that the aggresomes clog the lysosome, preventing it from acting normally in other parts of the cell. As she says, there are a lot of options to explain how autophagy functions in HD. However, autophagy research is relatively new, so a lot remains to be done.

There are a lot of experimental models used in the lab, and Dr. Riley mentions a specific tissue culture cell line that comes from mouse nerve cells. These cells have the altered huntingtin protein, and it is under the control of a “conditional promoter”. By adding or taking away a certain chemical called tetracycline, researchers can turn the production of the altered huntingtin protein either on or off at will. This is a very powerful model system because it allows you to produce enough altered huntingtin protein for HD to begin. Then, you can turn off production of the protein, and look at how autophagy is clearing it out of the cell. Dr. Riley particularly likes working with cell lines like these. She thinks it is a good model system for preliminary studies before taking her findings and applying them to more complex models, such as mice. But she has a few concerns. She recognizes that mice nerve cells do not behave the same way as human nerve cells, so she wonders if findings from model systems like cell lines and mice will apply to humans well.

Last Modified: 09/11/2007

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