Huntington's Disease (HD) Center Without Walls-Overview The theme of this long-standing and very successful HD Center is investigation of the HD pathogenic process, beginning at its starting point, the genetic defect and proceeding to its inevitable clinical and neuropathological consequences. As in the past, HD Center investigators continue to approach the problem interactively, creating a synergistic energy that has fostered great advances. In past cycles, we mapped the HD defect, identified it as a CAG repeat expansion, discovered huntingtin aggregates as a new pathologic correlate, developed genotype-phenotype correlations to guide further investigations, and created accurate genetic mouse models of HD. In this renewal cycle, we place a major focus on defining factors that modify HD pathogenesis, as these represent valid targets for the development of rational therapeutics badly needed in HD. Project 1 (Gusella): Genetic and Chemical Modifiers in HD will use molecular genetic analysis to identify modifiers of HD initiation and pathogenesis and characterize their modes of action. Project 2 (Myers): Genetic Studies of Huntington's Disease will perform statistical genetic and bioinformatics analyses to complement molecular efforts in Projects 1 and 3 in defining genetic modifiers of HD onset, progression and disease manifestations. Project 3 (MacDonald): Modifiers of Steps in HD Pathogenesis will test huntingtin interacting proteins as potential HD modifiers and will utilize the accurate genetic knock-in mouse model of HD to define genetic modifiers of pathogenesis. These projects will be supported by cores for Administration (Gusella), Small Molecule Screening (Stein), and Genotyping (MacDonald). Collectively, our studies represent a concerted effort to understand HD and promise to continue the achievements of this HD Center. They also have a realistic potential to benefit HD patients, as targets and compounds will be investigated in a true drug development paradigm (LEAD optimization, animal testing, human trials;outside the scope of this grant) by the non-profit High Q Foundation, which has made a major organizational and financial commitment to capitalize on basic science findings from academic studies such as those of this long-standing HD Center.