HD research news - medical research into treatment & prevention

Heat Shock Proteins, Molecular Chaperones and High-Throughput Screens top llst of new research Initiatives

The HDSA Coalition for the Cure met for its 7th semi-annual Research Conference in Vancouver, BC, Canada, from March 30 - April 1, 2000. Seventy-two participants, including Coalition Investigators, Sub-Committee members and scientific colleagues, met to discuss primarily unpublished preliminary research. Kicking off the conference was the Coalition Symposium, which invites professionals who have expertise in research areas that impact HD, outside the Coalition, to contribute their knowledge. Four guest speakers, representing both the pharmaceutical industry and academia, were invited to provide a broader spectrum of knowledge.

Also present for the first time were HDSA’s grant and fellowship recipients, thus providing an opportunity for HDSA’s two research branches to meet and share in an atmosphere charged with excitement about the latest research data. "The excitement generated by the presence of our Grant and Fellowship recipients can’t be expressed" said HDSA Chairman of the Board, Donald A. King "The electricity in the air, the new ideas and avenues for research just erupted within that room. It was an exciting moment in HD history"

Topics garnering the most attention and prolonged discussion included protein aggregation, chaperones, heat shock proteins and caspases. Protein aggregation, or the accumulation of mutant protein (huntingtin) in the cell and nucleus, has been a topic of extensive research. Recent studies are now directed at attempting to prevent or stop altogether this buildup. While it is still unknown whether aggregation plays a causative role in the disease, or is a by-product of the disease pathway, it remains unquestionably a disease hallmark whose function must be further investigated.

Molecular chaperones, or more simply chaperones, are proteins that help other proteins to fold properly. A protein has a linear structure composed of a sequence of amino acids, similar to the letters that create words. For a protein of any kind 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, a specific sub-group of chaperones, known as heat shock proteins, assist proteins to fold into their active 3-D structure and can, when needed, repair proteins that have misfolded. Heat shock proteins impact HD when the huntingtin protein, which contains the disease conferring expanded CAG repeat, becomes misfolded. If chaperones can assist mutant huntingtin protein to fold properly, it may not continue along a path that leads to degeneration. Early data indicates that experiments that increase this chaperone activity lead to a decrease in neurodegeneration in cell models, fly and worm models of polyglutamine repeat disease.

In addition to aggregations and chaperones, caspases are an area of intense study. Caspases are proteins that play a role in cell death. When a cell undergoes programmed cell death, or apoptosis, enzymes (proteases termed caspases) are activated in order to implement the chopping process in the proteins (like huntingtin) of a cell. Research has proven that by inhibiting caspase activity, you can delay the onset of HD in transgenic mice. Several Coalition labs presented their work on how different caspases affect neurodegeneration.

In addition to each presentation by Coalition labs, the Investigators and Sub-Committee members met in a closed session to determine the future goals for the Coalition and the direction for new HD research initiatives. One of the most exciting objectives to come out of the closed-door sessions was to increase in the number of high-throughput screens in development. A high-throughput screen is a large-scale, automated set of experiments that attempt to screen, or test, a large number of compounds (known as a library) against a specific assay. An assay is a method used to determine whether your work has caused the desired effect in an experiment, such as curtailing the aggregation process or preventing cell death.

An example of a high throughput screen is the work currently being conducted by HDSA sponsored investigator, Dr. Erich Wanker, at the Max-Planck Institute in Germany. Dr. Wanker is screening a library of over 180,000 unknown compounds for their effect in test tubes containing mutant huntingtin protein in order to determine whether some of the compounds might prevent protein aggregation. Early data are promising. As a result, members of the Coalition Sub-Committee are advocating for HDSA to fund more high-throughput screens that might apply to cell models or fly models as well as urging Coalition investigators to design assays that might build upon or supplement Dr. Wanker’s protein aggregation assay.

The HDSA Coalition for the Cure has set a research goal to fund three high-throughput screens by 2001. As these screens are extraordinarily expensive to implement, these new goals pose a challenge to us all to develop the resources required to make these goals a reality.

But the challenge to fund new and exciting research should be readily accepted by our HD friends and family. These new research initiatives represent a dramatic shift toward therapeutics, the next step along the road to a cure for HD. As Dr. Christopher A. Ross, M.D., Ph.D. stated "I see the cure as the product of a series of steps that we (HDSA) take toward the ultimate goal." Research in the past has concentrated on our need to understand the dynamics of the disease. The time has now arrived for HDSA to begin to diversify the research initiatives and projects that we fund. While it is vital that we continue to invest in basic research, which increases our understanding of the disease pathway, we are just now beginning to recognize how that basic understanding can be taken from the research bench to the patient’s bedside.

Coalition Investigators left Vancouver with a renewed sense of purpose and a strong desire to apply many of the basic research initiatives that have come out of Coalition collaborations to new therapeutics. Many will report on their progress at the next HDSA Coalition for the Cure meeting which will be held October 24-25, 2000 in San Diego, CA at the Hilton La Jolla Torrey Pines. This will also be held in conjunction with the Huntington Study Group’s annual meeting.

• With thanks to the HDSA for this report.