Research Frontiers
Part 2

Research

Dr. Morimoto’s lab looks at HD from the very beginning of the disease cascade. He describes the disease cascade process like this: a protein with an expanded polyglutamine chain (which is toxic) impairs cells and their function over time, eventually leading to nerve cell death. His lab studies the beginning of the cascade, asking the question “What goes wrong in protein quality control?” Dr. Morimoto believes that protein quality control is one of the cell’s most ancient mechanisms. In the very first forms of life, RNA was the main hereditary genetic material in cells, instead of DNA as it is now. In this “RNA world,” cells were much less complex. In order to survive all of the sources of stress they were subjected to, they must have had very good protein quality control mechanisms. These mechanisms have been preserved in the “DNA world” of the present day. Additionally, the question of protein quality control is especially intriguing because protein misfolding is common among neurodegenerative diseases, HD included. Dr. Morimoto’s findings have the potential to be useful in the study of other neurodegenerative diseases. “The implications are broad,” he says of his research program.

Why does Dr. Morimoto focus on HD if is research is so broad? As he puts it, “HD is a leader as a genetic dominant.” As opposed to some other neurodegenerative diseases, HD is a disease that is easy to identify by using genetics. The presence of at least one allele for the altered Huntingtin gene always indicates a person will have HD. The genetic link is not so clear in other neurodegenerative diseases. For example, only 2% of cases of amyotrophic lateral sclerosis are actually related to an inherited genetic mutation. These cases are called Familial Amyotrophic Lateral Sclerosis, or FALS. In short, using HD to study protein quality control is valuable because it has straightforward genetic links, and it has broader implications for other neurodegenerative diseases.

The Morimoto Lab has also created C. elegans models related to tau-pathologies, amyotrophic lateral sclerosis, and other polyglutamine diseases besides HD. All of these models help to understand the genetic basis of protein misfolding by comparing the different molecules associated with each of these diseases. In addition to C. elegans, the lab uses use in vitro studies and tissue culture (cells grown in a Petri dish), among others as model systems to answer these questions. Dr. Morimoto describes these multiple approaches as “the only way to run a lab.” These different models allow the lab to run multiple tests on hypotheses, so they can be much more confident about their results. For example, Dr. Morimoto says that there are certain advantages to doing experiments with tissue culture, but that they need to be verified in studies using whole organisms. In doing this, they can see if they get the same in an entire living animal, not just isolated tissue in a Petri dish, and the C. elegans model is a good way to test any hypothesis in his lab.

Dr. Morimoto also discusses the pharmacological studies done in his lab. In these studies, the researchers discover small molecules involved in protein folding. These molecules could serve as a basis for therapeutic drugs or therapy treatments. In a large collaborative effort with 26 other laboratories worldwide, the Morimoto lab helped identify a small molecule called celastrol, from a plant often used for its anti-inflammatory properties in Chinese herbal medicine. Celastrol was identified because it can activate important genes involved in the heat shock response and elevate the level of molecular chaperones in the cell. These molecular chaperones could help protect the cell from the damage caused by misfolded proteins. Members of the Morimoto lab are now working with Dr. Richard Silverman, a professor in the Department of Chemistry, to discover the specific structure of celastrol and how it works with other proteins to activate the heat shock response. Dr. Morimoto believes a detailed understanding of exactly how celastrol works is important before it is turned into a therapy drug and put into clinical trials. However, the potential of celastrol certainly seems promising.

Last Modified: 03/28/2006

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