HD research news - medical research into treatment & prevention

Recent fruit fly research in HD

Dr. Seymour Benzer’s lab at the California Institute of Technology has published some recent findings that benefit Huntington’s disease research.

In a fly, or Drosophila, model of trinucleotide repeat disease (Huntington’s is one of many trinucleotide repeat diseases), they looked for proteins which might affect the toxicity which derives from an expanded polyglutamine tract. They found that the fly homologue of the human heat shock protein, Hsp40 could delay or suppress cell death caused by a protein with expanded polyglutamine. Heat shock proteins are a subgroup of a set of proteins called chaperones. Chaperones are proteins which help other proteins to fold into their active three-dimensional structure.

Proteins have a linear structure made of a sequence of amino acids, much like the letters which make up a sentence. For a protein to work properly, it must fold into a three dimensional configuration, which then allows it to interact with cell receptors, cellular machinery, and other proteins. Often it is a specific sub-grouping of chaperones called heat shock proteins which help proteins to fold into their active 3-D structure, and also can help fix proteins which have misfolded. They are implicated in Huntington’s disease because the huntingtin protein, when it contains the disease-conferring expanded CAG repeat, gets misfolded and sets off a series of pathological events. If chaperones can help the mutant protein fold properly, perhaps it won’t go on to cause degeneration. Early data show that experiments that increase chaperone activity cause a decrease in neurodegeneration in fly and worm models of Huntington’s disease.

In addition to the Benzer lab, Dr. Nancy Bonini’s lab at the University of Pennsylvania which HDSA funds, also works on fly models of trinucleotide repeat disease. The lab recently worked on a fly model of ataxia, another polyglutamine repeat disease, and found that overexpression of two heat shock protein (Hsp) molecular chaperones prevented aggregation of the mutant protein ataxin-3. While this study did not involve the huntingtin protein, it is a very similar mechanism of polyglutamine repeat disease.

Thus, both labs are finding proteins which modify the CAG gene mutation. Since homologs (homologues) to these fly proteins are found in humans, it is a research path which scientists are excited to follow. The next step is to find more interacting or modifying proteins, and then to start testing them in the mouse models and cell models of the disease.

More investigators are now starting to look at how all molecular chaperones, and specifically heat shock proteins, affect the mutant huntingtin protein.

This kind of research represents a shift towards therapeutics. At one point, we were just trying to understand how the disease came about, and what it was doing to the cells. While we are still researching in this manner, we are now adding the very important layer of searching for the ways to prevent the pathology. It all serves to engender more excitement for research in this field, and quicker and more frequent discoveries.

• With thanks to the HDSA for this report.