Research

PROTEIN FOLDING

Elise Kikis studies the aberrant proteins that underlie neurodegenerative diseases such as Huntington’s Disease. Huntington’s Disease is one of several autosomal dominant disorders in which a polyglutamine (polyQ) expansion leads to “toxic gain of function” caused by the adoption of a misfolded or aggregated state associated with proteotoxicity. Contact her for more information about research opportunities in her laboratory.

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Overview:

The model system employed in the Kikis Lab is the nematode C. elegans. This well-studied model has the advantage of a simple body plan, a short generation time, ease of culturing in the laboratory, large numbers of readily available mutant strains, and the ease of generating transgenic lines.

We have generated three sets of C. elegans lines that each express a human disease-associated protein. The proteins have been tagged with a fluorescent marker allowing us to visually assess the localization and the aggregation of these important proteins under different genetic and environmental conditions.

We have found that different proteins, all associated with neurodegenerative diseases, and all harboring a polyglutamine expansion, have different aggregation properties when expressed in C. elegans. These differences are reminiscent of differences in disease symptoms, and lead us to ask what it is about the biology of the cell that makes it respond differently to a polyQ expansion in the context of one protein compared to another.

Research Data

Fixed nontransgenic (WT), YFP alone, hARNTQ35, and hARNTQ132 animals were stained with rhodamine-labeled phalloidin and visualized with a confocal microscope.  The YFP channel shows localization of YFP or YFP-tagged hARNT and the phalloidin channel shows muscle filament integrity. Schematic representations of expressed constructs are shown.  Expression of hARNT-YFP is under control of the muscle-specific promoter, unc-54.

Undergraduate Research Opportunities: There are plenty of opportunities for motivated students to conduct research in the laboratory. While research takes a significant amount of time and commitment, it can be a highly rewarding endeavor, and a memorable component of one’s undergraduate career.

Current research questions include:

Does protein context influence the ability of a cell to launch a protective response to protein damage? Cells are constantly monitoring protein damage, which is often due to environmental stress such as heat shock. In the case of heat shock, which causes proteins to misfold, cells respond by turning up the expression of protective proteins known as molecular chaperones. We would like to know if cells turn up these same genes in response to certain polyQ containing proteins. Additionally, we would like to ask whether the expression of certain polyQ proteins actually impairs the ability of the cell to respond to a secondary assault such as heat shock.

Does protein context influence the genetic/molecular interactions of polyQ-containing proteins? Previous studies have identified all the genetic interactors of the polyQ peptide in C. elegans. If the protein context in which the polyQ tract is embedded influences these genetic interactions, we can find out by testing the previously identified modifiers against our new models that have the polyQ tract in the context of an actual disease-related protein.

Does protein context influence the tissue-selectivity of polyQ proteins in C. elegans?  Currently, we have only examined expression in muscle cells, but what happens to other tissues when they are expressing polyQ-containing disease-associated proteins? Are some tissues more sensitive than other tissues to polyQ proteins? Are some tissues sensitive to some polyQ proteins but not others?