Gene Expression Phenotypes for Identifying Modifiers and Treatments in Huntington's Disease
Principal Investigator: James P. Gusella, Ph.D., Massachusetts General Hospital, Boston
Co-Investigator: Marcy MacDonald, Ph.D., Massachusetts General Hospital, Boston
Current Status: Completed 2011
1. What questions did we asking in this DBP?
The gene responsible for Huntington's Disease has been identified but the mechanisms whereby the mutation(s) cause disease are not know. Can we identify the genetic modifiers of the disease, define the effects that they have and the stage in the pathogenic process at which they and candidate drugs act?
2. How did i2b2 help us answer these questions?
Sophisticated bioinformatics and genomic analytical tools and expertise will be crucial in helping to overcome the hurdles represented by this complex monogenic disease with its poorly understood multigenic modifiers.
3. What tools were developed from our work that will be of value to others?
The genomic and analytical tools customized for our work will become part of the genomic Hive Cell suite in the Clinical Research Chart (the plug and play architecture designed to enable clinical researchers to use existing data repositories for discovery research on diseases with genetic associations).
4. What new clinical discoveries do we anticipate may arise from our i2b2 project?
If we can identify a predictor of CAG triplet repeat length, this would provide a rational basis for screening small molecule libraries for potential efficacy in the treatment of Huntington's Disease.
Huntington’s disease (HD) is a dominant late-onset neurodegenerative disorder caused by the presence of an expanded polyglutamine tract that confers a novel “gain-of-function” property on the large huntingtin protein. The pathogenic process in HD can be viewed as a cascade triggered by the presence of the polyglutamine tract in full-length huntingtin protein (which is expressed throughout life in both neuronal and non-neuronal cells) and culminating in the dysfunction and death of medium spiny striatal projection neurons (and some others), with the consequent clinical manifestations of a characteristic, progressive movement disorder, psychiatric abnormalities and cognitive decline. Our goal has been to define the identity and relative order of events on this cascade, with a view toward developing therapies that block the trigger itself or steps shortly thereafter. This work has led to the creation of a precise genetic model of HD in the mouse, characterization of biochemical alterations caused by full-length huntingtin in these mice and in patient lymphoblast cell lines, structural examination of huntingtin protein and drug screening for the “gain-of-function” property conferred on huntingtin by the polyglutamine tract. We have been guided by genotype-phenotype studies that have established clear genetic criteria for the polyglutamine-mediated triggering mechanisms that permit evaluation of the relevance of model systems findings to the human disease. Using these, we are in a strong position to make significant strides in elucidating early events in pathogenesis and translating these findings into potential drugs for testing in preclinical models and in human patients. We have already identified evidence for genetic modifiers that alter the HD pathogenic process in human patients and drugs that reverse mutant protein-associated phenotypes in cultured cell models. We now need to identify these modifiers, define the effects that they have and the stage in the pathogenic process at which they and the candidate drugs act. Sophisticated bioinformatics and genomic analytical tools can be now crucial in helping to overcome the hurdles that still face us and thereby to accelearate the development of a treatment for this devastating neurodegenerative disorder.
1. To use microarray expression analyses to define sets of genes whose expression is quantitatively altered in HD.
2. To use microarray expression analyses of striatal tissue from hdh knock-in mice of different ages to define the temporal changes in pathways as the pathogenic process progresses, as a means of defining steps in the pathogenic cascade in vivo and of highlighting potential surrogate markers.
3. To test whether the context in which the polyglutamine tract is presented, i.e., the nature and precise sequence of the adjacent amino acids and its capacity to interact with other proteins, can act to modify the pathogenic conformational property of the huntingtin polyglutamine tract.
4. To systematically compare expression patterns of lymphoblastoid cell lines from sibs concordant and discordant for deviation from the exppected age at neurological onset due to the action of modifer genes.
- Using the expression signatures of white blood cells from HD patients, gene groups have been identified whose signatures vary with length of the CAG repeat.
- By comparing the white blood cell data from the HD cell lines to that of expression in murine models of HD, we observe that the HD CAG repeat appears to alter extra-mitochondrial energy homeostasis pathways.
- Gusella JF, MacDonald ME. Huntington's Disease: Seeing the pathogenic process through a genetic lens. Trends Biochem Sci. 2006;31:533-40. PMID:16829072.
- Lee JM, Ivanova EV, Keongi IS, Cashorali T, Kohane I, Gusella J and MacDonald M. Unbiased gene expression analysis implicates the huntingtin polyglutamine tract in extra-mitochondrial energy metabolism. PLoS Genet. 2007;3(8):e135. PMID:17708681.
- Gusella JF, MacDonald M. Genetic criteria for Huntington's Disease pathogenesis. Brain Res Bull. 2007;72:78-82. PMID:17352930.
- Jacobsen JC, Gregory GC, Wode JM, Thompson MN, Coser KR, Murthy V, Kohane IS, Gusella JF, Seong IS, MacDonald ME, Shioda T, Lee JM> HD CAG-correlated gene expression changes support a simple dominant gain of function. Hum Mol Genet. 2011;20(14):2846-60. Epub 2011 May 2. PMID:21536587.
- Fossale E, Seong IS, Coser KR, Shioda T, Kohane IS, Wheeler VC, Gusella JF, MacDonald ME, Lee JM. Differential effects of the Huntington's Disease CAG mutation in striatum and cerebullum are quantitative not qualitative. Hum Mol Genet. 2011;20(21):4258-67. PMID:21840924.