In September 2013, several HOPES student researchers attended the Huntington’s Disease World Congress, held in Rio de Janeiro, Brazil. Summaries of the all the sessions attended can be found in the Conferences and Conventions section of our site.
The HOPES trip to the 2013 World Congress received partial support from the Bingham Fund for Innovation in the Program in Human Biology.
On the first day of the HD World Congress in Rio de Janeiro, four speakers each gave a lecture on the basic science behind current research on the search for a treatment and cure for Huntington’s disease. The speakers were Elena Cattaneo from Italy, Tiago Fleming Outeiro from Germany, Marcy E. MacDonald from the United States, and Ignacio Munoz-SanJuan from the United States.
The lecture given by Elena Cattaneo was entitled “What Do We Really Know About Huntington Function in HD?” She explained that huntingtin is an important protein during embryonic development, such as during gastrulation, and has key functions in the living brain. The number of CAG repeats has grown in a linear progression in animals, beginning with just one repeat in sea urchins 800,000,000 years ago and increasing as multi-cellular organisms evolved into more complex beings. One example of the importance of CAG repeats is in the formation of rosettes, a special kind of grouping of cells that give structural support to neurons, during neural tube creation in the nervous system. If there are too many or too few CAG repeats in the huntingtin protein in the nervous system, rosettes will not form. Cattaneo also gave a similar example about ADAM10, which is critically important for use in the brain but is overproduced in the caudate of HD brains. Her overarching message emphasized the dynamic nature of huntingtin, a subtle point often lost in studies of the mutated version of the protein.
The next lecture by Taigo Fleming Outeiro was entitled “Molecular Chaperones in HD.” Molecular chaperones are quality-control mechanisms that monitor and regulate protein folding and degradation. Outeiro’s talk focused on the big research questions concerning the involvement of these molecular chaperones in what causes proteins to misfold, as well as when and why neurons become dysfunctional and die as a result of this misfolding. The example chaperone discussed was DJ-1, which is associated with familial Parkinson’s disease and has an increased presence in the cortex and cerebellum of HD brains. Some of its roles as a chaperone include preventing apoptosis (or breakdown) of misfolded proteins that still function and sensing oxidative stress in cells. In mouse, fruit fly, and yeast models, DJ-1 and other similar molecular chaperones (also known as orthologues) have been shown to alleviate mutant HD toxicity by refolding or rescuing misfolded proteins. Outeiro concluded that because of this research, there is hope that molecular chaperones could be used to regulate protein-misfolding disorders in the future.
Marcy MacDonald gave the next lecture, which was entitled “Is HD also a prion disease?” She immediately clarified that HD is NOT a prion disease because it does not involve Prion Proteins (or PRNPs) and it is much more common than prion diseases, such as Creutzfeldt-Jakob disease. Given that context, MacDonald emphasized that there is much more hope for finding a cure for HD than for various prion diseases because the research could take so many more routes. For example, MacDonald noted that while HD is predominantly known for being a neurodegenerative disorder that attacks medium spiny neurons in the striatum in the brain, the mutant protein is indeed in all cells and tissues of the body. She suggested that perhaps this means that the HD protein triggers an effect in all cells and tissues instead of just in the brain. For instance, the amount of energy being produced in lymphoblastoid and neuronal progenitor cells decreases as the amount of HD repeats increase in an organism. This could impact the affected organism throughout the entire span of its existence, not just after symptoms have begun. MacDonald hoped that key insights into new ways of looking at HD, such as how the entire HD process works from beginning to end in the whole body, could stimulate a variety of fresh ideas for research.
The final lecture, given by Ignacio Munoz-San Juan, was about “Synaptic Mechanisms in Huntington’s disease – Understanding the HD Brain to Develop Novel Therapeutics.” Typical therapeutic approaches include attempting to modulate mutant HD expression, modulating chemicals that decrease toxicity in the brain, and modulating mechanisms such as energy-production and protein death, which affect the organism overall. To find new therapeutic approaches, studies are being conducted observe HD as it progresses in people, in various animal models, and in specific cell-types in the body. For example, PDE10 is a powerful activator of striatal transcription and it enriches medium spiny neurons in the striatum. After observing that PDE10 is expressed more in HD brains, researchers have started testing to see how PDE10 can be used to rescue dysfunctional medium spiny neurons in HD brains and are hoping to be Phase 2 of clinical trials with PDE10. This is just one example of how observational studies have led to new research in the lab to treat or cure HD.
These four lecturers each gave a fantastic overview of the basics of current research in the search for a treatment and cure for HD, especially given their variety of backgrounds in science. There is indeed hope out there.