Research Frontiers

Research Methodologies

Out of the hundreds of scientists studying Huntington’s disease (HD), few share the same research methodology or approach. Yet every one of their studies is an invaluable contribution to the fight against the disease. The goal of this chapter is to familiarize our readers with the wide variety of methodologies for studying HD, as well as the scientists who implement them. Through a series of interviews with researchers, we hope to give an accurate, multi-dimensional picture of the different resources and methods that they use to study HD.

A long cascade of events must take place before someone actually displays the symptoms of the disorder. First, that person must have the HD allele in his or her DNA. This HD allele must then give rise to an altered form of the huntingtin protein. Altered huntingtin will then negatively influence other proteins in the nerve cell. Over time, these negative influences will cause the nerve cell’s environment to become damaged. The damaged nerve cell will have impaired mitochondria and be unable to communicate normally with other nerve cells. Impaired mitochondria will cause an imbalance of certain chemicals in the nerve cell, especially harmful free radicals that contribute to nerve cell degradation. Communication problems will manifest themselves in the nerve cell’s vulnerability to otherwise harmless neurotransmitters like glutamate, causing the glutamate to be toxic to the nerve cell. In addition, the altered nerve cell environment will elicit the production of certain proteins that will cause apoptosis, or programmed cell death. When this series of events causes the death of nerve cells in the basal ganglia regions of the brain, the critical motor, cognitive, and psychiatric functions that they support begin to suffer, and the individual begins to show the symptoms of HD. (For a broad overview of HD and its symptoms, click here.)

Because each stage of this disease cascade is necessary to ultimately result in HD, researching ways to stop the cascade at any of its stages could be very beneficial. Let us take a brief look at some examples of research at various stages of the disease cascade. (Note: Some forms of research do not fall under a particular stage of the disease cascade. This includes stem cell research (to learn more about stem cell research, click here) and research into substances that only seek to combat the symptoms of HD rather than the underlying disease process. The following is in no way an exhaustive list; there is research at each level of the disease cascade that looks into many chemicals, proteins, and processes that are not mentioned here. Also note: Because scientists are still trying to determine the exact sequence of events in the cascade, the following is a rough estimate of what occurs at each stage.)

• The disease cascade begins with the expanded Huntington’s disease CAG allele (the version of the Huntington gene that causes HD). There are many steps in the complex process by which the gene makes the huntingtin protein. Many of these steps, if altered correctly, could result in the expression of the normal huntingtin protein instead the altered one. In this regard, researchers are studying proteins like HDBP1 and HDBP2, which play a role in the transcription of the Huntington gene. Other researchers are studying techniques like gene silencing and RNA interference (RNAi) with a molecule called short interference RNA (siRNA).
• At the next stage of the disease cascade, many researchers look at the huntingtin protein itself, trying to determine why having a few extra copies of the amino acid glutamine turns this otherwise normal protein into a very damaging one. Researchers like Marcy MacDonald and Elena Cattaneo (whose research appears later in this chapter) are investigating the process by which huntingtin becomes mutated, as well as the role that the normal protein plays in the nerve cell (termed huntingtin normal function). In addition, some researchers study how proteins like SUMO-1 affect the folding of huntingtin and test chemicals for their effectiveness in combating huntingtin toxicity.
• Another step further in the disease process, many researchers try to identify the components that damage the nerve cell environment (and lead to eventual mitochondrial impairment and glutamate toxicity). Some may concentrate their efforts on huntingtin protein aggregates, although it is still not known whether these are a cause of HD symptoms or simply a result of the disease. Others may study how the functions of CREB-binding protein (CBP) and many other proteins are affected by the altered huntingtin protein. These proteins may be a part of critical processes within the cell, so a great deal of research also goes into improving their functions or finding replacements for them. Scientists also investigate transcriptional dysregulation, a phenomenon that occurs when the altered huntingtin disrupts the normal transcription process within vulnerable nerve cells. At a later stage of the disease cascade, some researchers seek ways to repair the damaged mitochondria in the nerve cells, so as to maintain proper calcium levels and inhibit the production of free radicals.
• Finally, some researchers study HD by directing their efforts toward the end of the disease cascade. Certain researchers seek ways to combat the activity of caspases, which lead to apoptosis. Other researchers test chemicals to help eradicate free radicals once they are produced. Still others study glutamate receptors and the genes that make them (like GRIK2 [Glu6]), hoping to discover a way to make glutamate less toxic to the damaged nerve cell.

If a substance or technique were able to completely inhibit a given stage of the HD disease cascade, subsequent events in the cascade would never occur, and the person would never show the signs and symptoms of Huntington’s disease. In the event that a substance or technique fit this description, it would likely be called a cure for HD. However, because current treatments for HD only partially inhibit a stage of the cascade (or simply fight symptoms rather than the underlying mechanism), the chain of events leading to the disease still occurs. Many researchers believe that the cure for HD will not rely upon a single magic bullet, but rather a combination of multiple substances and techniques. Thus, each research group’s approach to studying HD is like a small solution to a much larger puzzle. While their methodologies run the gamut of creative investigation, we can all hope that someday their findings will fit together to solve the HD puzzle and provide a cure.

Note: The views expressed by the following groups of researchers are presented for your consideration and do not necessarily represent the opinions of the HOPES team.

HDSA Centers of Excellence	A discussion of what it means to be an HDSA "Center of Excellence"
Chapter 1, Section 1	Drs. James Gusella and Marcy MacDonald Molecular Neurogenetics Unit, Massachusetts General Hospital Charlestown, MA
Chapter 1, Section 2	Dr. Diana Rosas Massachusetts General Hospital Charlestown, MA
Chapter 2	Dr. Elena Cattaneo Department of Pharmacological Sciences and Center of Excellence on Neurodegenerative Diseases, University of Milan Milan, Italy
Chapter 3	Melinda Kavanaugh and Dr. Samer Tabbal HDSA Center of Excellence - Washington University Medical Center St. Louis, Missouri
Chapter 4	Dr Rick Morimoto Department of Biochemistry, Molecular Biology and Cell Biology Northwestern University Evanston, IL
Chapter 5	HDSA Center of Excellence at Columbia University New York State Psychiatric Institute New York, NY
Chapter 6	Interview with Dr. Ron Kopito and Dr. Brigit Riley at Stanford
Chapter 7	Johns Hopkins Center of Excellence

Last Modified: 11/04/2007

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