Dr. Ross discusses a few of the research projects conducted in his laboratory. He explains that the primary purpose of basic research is to identify biological targets for HD, and to develop those targets into treatments. For more on the process of going from basic research to a treatment, click here. As such, his lab focuses their research projects around potential biological targets for HD, and mostly on the huntingtin protein itself.
1) One area of current studies focus on how huntingtin aggregates are formed, and at what point these aggregates are toxic and cause nerve cell death. They have hypothesized that the larger aggregates or neuronal inclusions are not the most toxic molecules, but rather that the intermediates proteins in this aggregation pathway (the early aggregates) may be the most lethal form. As such, they may be the best molecules to target for future therapies. For more information on huntingtin aggregation, please click here.
Dr. Michelle Poirier, another faculty member at Psychiatry at the Johns Hopkins University School of Medicine, is doing studies in her own laboratory to investigate the shape or molecular structure of these intermediate huntingtin proteins. One of the most recent theories of how huntingtin protein aggregates are shaped describes them as made up of a series of folded strands of amino acids, with each strand composed of seven or eight glutamineamino acids. In a paper published in 2005, Dr. Poirier collaborated with the Ross lab to create two tissue culturemodels based on this theory. They confirmed that the proposed structure does indeed occur, and that there is a correlation between the presence of this type of huntingtin aggregate in the tissue culture cell and the presence of cell toxicity. However, they suggest that it is entirely possible that the toxicity is not caused directly by these aggregates, but rather that any of the kinds of intermediate species formed throughout the aggregate pathway may be responsible for toxicity instead.
2) Another project in the Ross lab looks at what kinds of proteins are involved in cutting the huntingtin protein into fragments. This process is also implicated in nerve cell toxicity in HD - it is thought that a fragment of huntingtin is actually more toxic to the cell than a full-length huntingtin protein. For more information on huntingtin protein fragments, please see figure P-2 here. In collaboration with Dr. David Borchelt and his laboratory at the University of Florida's College of Medicine, Dr. Ross' lab developed one of the initial transgenic mouse models of HD. Dr. Ross's lab has used this mouse model to look at which enzymes play the largest role in generating toxic fragments of huntingtin protein. In collaboration with Dr. Michael Hayden's laboratory they have already determined that caspase-6 is one of the most commonly involved enzymes in huntingtin fragmentation (please click here for a HOPES article on that finding), but they are looking at the role of other caspases and calpains (another family of proteases) as well.
Tamara Ratovitski, a member of the Ross lab, leads a related project using tissue culture models to look for the specific points in the chain of amino acids in the HD protein where fragmentation occurs. She wants to understand exactly how many fragments are generated by each type of protease, and how long they are. The goal is to target the most important proteases for inhibition, which will reduce the number of fragments and (presumably) cell toxicity.
3) A third project at the Ross lab looks at the affects of the mutant HD protein upon gene transcription. It is thought that the altered huntingtin protein changes the patterns of how genes are transcribed and translated, especially the genes that are key for a cell's survival- and this may contribute greatly to toxicity in HD. Several years ago, Dr. Ross' lab identified an unusual interaction between the mutant HD protein and the CREB-binding protein (also known as CBP), a smaller regulatory protein that is key for cell survival. For more information on the role of CBP in HD, click here.
Currently, the lab is following up this project with another group of studies intending to demonstrate a direct connection between the altered huntingtin protein, altered gene transcription, and cellular toxicity. It may be that the interaction between CBP and the altered huntingtin protein is one of a group of similar interactions between proteins involved in gene transcription and the altered huntingtin protein. If their research conclusively demonstrates that altered gene transcription does lead to cellular toxicity, one possible therapeutic intervention would be to use HDAC inhibitors. For more information on the potential role for HDAC inhibitors, please click here.
When asked what he thinks about the role of basic scientific research in respect to the larger body of HD research, Dr. Ross illustrates his opinion by discussing what goes on at the Baltimore Huntington's Disease Center. Dr.Wenzhuan Duan, an assistant professor in the Department of Psychiatry and Behavioral Sciences works on research in Huntington's and Parkinson's disease. He takes biological targets identified through basic research on HD, and develops potential therapeutic drugs based on these findings. For more information on the process of drug research and development in HD, click here. They have developed a tissue culturemodel using nerve cells with the altered huntingtin protein that can be used to test potential therapeutic compounds to see if they might be useful for treating HD.
Dr. Ross emphasizes that another one of the major goals in doing therapeutic research is not only to cure HD, but to delay its onset. The idea would be to intervene by using treatments before the cognitive, motor, or behavioral symptoms actually appear. Members of the BHDC have already demonstrated that a great deal of neurodegeneration occurs before symptoms actually appear, so it would be effective if treatment occurred before the identifiable "onset" of symptoms to prevent or delay them. The Center has submitted a grant to conduct a phase II clinical trial to look at the effects of coenzyme-Q10 on presymptomatic HD patients, to see if it does in fact, delay the onset of symptoms. For more information of co-enzyme Q-10, please click here. The focus on research and treatments for presymptomatic HD patients is a very new direction for the Center, and appears to be a promising one.
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Rosenblatt A, et al. The association of CAG repeat length with clinical progression in Huntington disease. Neurology. 2006;66(7):1016-20. This study demonstrates that individuals with the smallest number of trinucleotide repeats appear to have the best prognosis
Reading S, et al. Functional Brain Changes in Presymptomatic Huntington’s Disease. Ann Neurology 2004;55;879-883 The 2004 publication demonstrating that there are significant structural changes in the brain in presymptomatic HD patients.
Rudnicki DD, et al. Huntington’s Disease Like-2 Is Associated with CUG Repeat-Containing RNA Foci. Ann Neurology 2007;61;272-282 A follow-up study on HDL-2 demonstrating that it affects RNA function, and this may contribute to cell toxicity in HDL-2.
Schilling G, et al. Characterization of Huntingtin Pathologic Fragments in Human Huntington Disease, Transgenic Mice, and Cell Models. J Neuropathology 2007. Vol 66, No. 4; 313-320 This publication demonstrates the location of significant sites of huntingtin fragmentation.
Poirier MA, et al. A Structure-based analysis of huntingtin mutant polyglutamine aggregation and toxicity: evidence for a compact beta-sheet structure. Human Molecular Genetics, 2005. Vol. 14, No.6: 765-774. This paper discusses the models for huntingtin protein aggregate structure, and further confirming the beta-strand/beta-turn model of aggregation.
Wang W, et al. Compounds blocking mutant huntingtin toxicity identified using a Huntington’s disease neuronal cell model. Neurobiology of Disease. 2005;500-508. This paper discusses a tissue culture model that has been demonstrated to be a good method to screen potential therapeutic compounds for treating HD.
Last Modified: 08/05/2008
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