The identification of the genetic defect causing Huntington's disease (HD), which we accomplished during the past period of this grant, has moved research in this disorder into a new and exciting era. An immediate impact of the discovery has already been felt, as the measurement of CAG trinucleotide length in IT15 has provided a specific, reliable, direct HD diagnostic test that can be applied to problematic cases or to presymptomatic or prenatal diagnosis. What is more important, the finding has placed us at the genetic starting point of a pathway that leads from the expanded CAG repeat to the selective neuronal loss characteristic of the disorder. Hopefully, the eventual delineation of the steps in this pathway will provide a detailed understanding of HD pathogenesis, and may target specific processes for the development of rational therapies for treating this devastating disorder. It is our intention to begin this important trek by exploring the origin, behavior and immediate consequences of the expanded CAG repeat in the Huntington's disease gene. We will 1) use the extended Venezuela HD pedigree, in which HD is segregating on a single haplotype in hundreds of individuals, to address fundamental questions concerning the variability and behavior of the HD CAG repeat as it is passed from generation to generation; 2) determine the stage of spermatogenesis at which instability of the repeat occurs; 3) investigate the consequences of CAG expansion by developing a battery of immunologic reagents to delineate the basic characteristics of huntingtin, particularly to determine whether the CAG repeat is translated into polyglutamine; and 4) identify and characterize genes encoding proteins that interact with either normal or HD huntingtin. These studies will provide a detailed description of the behavior of the CAG repeat and may implicate a mechanism for its instability in HD. They will also provide a direct comparison of normal and HD huntingtin that will reveal whether the mutation acts at the RNA or at athe protein level. These studies will generate the knowledge and reagents necessary to proceed along the cascade of events leading to neuronal cell death.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
5P50NS016367-17
Application #
5215119
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
17
Fiscal Year
1996
Total Cost
Indirect Cost
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Biagioli, Marta; Ferrari, Francesco; Mendenhall, Eric M et al. (2015) Htt CAG repeat expansion confers pleiotropic gains of mutant huntingtin function in chromatin regulation. Hum Mol Genet 24:2442-57

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