Richard Myers, PhD

Huntington's Disease Research at Stanford

Dr. Myers’ research lab focuses on the genetics behind HD. Specifically, his lab has discovered a Huntington gene homolog in fruit flies, generated an HD model in mice, and investigated HD's effect on nerve impulses.

Drosophila homolog

While researchers have learned a lot about the genetic changes behind HD and the cellular changes that take place in nerve cells affected by HD, they still do not know much about the normal biological function of the huntingtin protein. Researchers hope that determining the normal role of huntingtin will help explain how the altered protein is involved in HD.

The first step towards the discovery of the normal function of huntingtin is to pinpoint the regions of the protein that actually carry out its job. These critical regions are collectively known as the functional domains. (See Figure 1.) If researchers can pinpoint these functional domains, they might be able to determine what chemical reactions occur at these sites, which might, in turn, lead to a better understanding of the protein’s biological function. To pinpoint these domains, researchers have investigated the huntingtin protein in various vertebrate animals – including the mouse, rat, pufferfish, and zebrafish.

Since the huntingtin protein probably performs similar duties in the cells of different species, the functional domains of the proteins are probably also similar. Therefore, researchers have looked for regions of huntingtin that are very similar in all of the different species. Unfortunately, the entire huntingtin proteins (not just the functional domains) in all the vertebrates listed above are almost identical, making it impossible to pick out regions that are more similar than others.

However, in 1999, Myers and his lab identified and sequenced a Huntington homolog in Drosophila melanogaster, more commonly known as the fruit fly. Since the fruit fly is so different from any of the vertebrates, they hoped that the majority of the huntingtin protein would also be different – with only the functional domains remaining similar between the fruit fly and the vertebrates.

Myers’ lab was successful in finding a Drosophila Huntington gene homolog and potential functional domains. The low overall similarity between the Drosophila huntingtin and the vertebrate huntingtin allowed them to pinpoint five regions of high similarity that are likely to be of functional importance to the protein. For this reason, future research will likely involve investigating these regions further.

HD Mouse Model

In 1999, Myers’ lab also generated a model of Huntington’s Disease in mice by introducing an HD-like mutation (by adding 72-80 CAG repeats) into the original non-HD allele of the Huntington gene. The HD model mice portrayed abnormal social behavior (specifically chronic aggressive behavior) equivalent to a mouse’s version of the early psychiatric HD symptoms, but did not exhibit neuron death or neurodegeneration. These results imply that the search for an HD cure may require an understanding of other dysfunctional processes, and not just neuron death. Further analysis of the HD model mice revealed that when the altered gene was passed from parent to offspring, the number of CAG repeats in the offspring was not constant (i.e. some offspring had more CAG repeats than either parent and some had less). CAG expansions were associated more frequently with paternal transmission while CAG reductions were more frequently associated with maternal transmission. (To learn more about expansion mutations, click here.)

HD and Nerve Impulses

After observing that their HD model mice showed neurological symptoms without developing nuclear inclusions or suffering neuron loss, Myers’ lab searched for other pathological effects of the altered huntingtin protein. They chose to investigate the physiology of the synapses in the hippocampus, an area of the brain that may be involved in cognitive and memory processing (both of which are disrupted by HD). Their research showed that while the synapses responded normally to a single stimulus, their responses were impaired after lots of consecutive stimuli. The impairment they found also suggested specific problems with the pre-synaptic nerve terminals. Further investigation revealed that the HD model mice, while normal in their ability to transmit nerve impulses at low frequencies of stimulation, released significantly less glutamate (a neurotransmitter) at even moderate frequencies of activation. This impaired ability to respond to stimulation frequencies that are well within the normal physiological range may potentially explain the early-stage symptoms of HD.

Myers’ research has already begun to solve many of the genetic mysteries behind Huntington’s Disease. In the future, his work will continue to investigate these differences between the normal and pathological functions of the huntingtin protein.

For more information on the research done by Richard Myers, visit the following website: http://www-shgc.stanford.edu/myerslab

For Further Reading:

1. Li, Z; Karlovich, CA; Fish, MP; Scott, MP; Myers, RM. “A putative Drosophila homolog of the Huntington’s disease gene.” Human Molecular Genetics 1999, 8(9): 1807-1815.
   A highly technical scientific paper on Myers’ research regarding the Huntington homolog discovery in fruit flies.
2. Shelbourne, PF; Killeen, N; Hevner, RF; Johnston, HM; Tecott, L; Lewandoski, M; Ennis, M; Ramirez, L; Li Z; Iannicola, C; Littman, DR; Myers, RM. “A Huntington’s disease CAG expansion at the murine Hdh locus is unstable and associated with behavioral abnormalities in mice.” Human Molecular Genetics 1999, 8(5): 763-774.
   A highly technical scientific paper on Myers’ research regarding the generation of the HD model mice.
3. Usdin, MT; Shelbourne, PF; Myers, RM; Madison, DV. “Impaired synaptic plasticity in mice carrying the Huntington’s disease mutation.” Human Molecular Genetics 1999, 8 (5): 839-846.
   A highly technical scientific paper on Myers’ research regarding HD’s effect on nerve impulses.

Last Modified: 7-5-03

An educational product of HOPES, not to be used in place of medical care. For more information about HOPES, click on the Logo. To contact HOPES with comments or questions, click here.