HUNTINGTON'S DISEASE MODELS

Johns Hopkins University, Baltimore MD

Investigators

Linked publications & trials

Abstract

DESCRIPTION (application abstract): We have generated transgenic mice expressing an N-terminal fragment of huntingtin with 82 consecutive glutamines, which develop neuropathological and behavioral abnormalities that model aspects of Huntington's Disease. In Specific Aim 1 we will characterize in detail the behavioral and neuropathological features of their phenotype in order to refine the design of therapeutic studies. Previous studies have indicated that the pathogenesis of HD may involve diminished mitochondrial function, leading to oxidative stress (increased superoxide production leads to increased peroxynitrite and nitration) and excitotoxic injury. To test these hypotheses, we propose a series of studies, in Aims 2-4, that are designed to enhance mitochondrial function (administration of Coenzyme Q 10), reduce excitoxic damage (administer Remacemide a glutamate antagonist), reduce oxidative stress (mate with mice that overexpress human wildtype superoxide dismutase), and diminish levels of peroxynitrite (mate with neuronal nitric oxide synthetase knockout mice). In each of the studies proposed, we will assess the impact of our manipulation on the onset and progression of behavioral abnormalities and on the severity of neuropathological changes. In addition, we plan to be in position to capitalize on the discoveries that may be made by our colleagues. For example, should studies in this project identify compounds that protect against mutant huntingtin in cell culture, we would test a subset of these compounds in our mice. Studies in the Genetics Core may identify new genes that are involved in the pathogenesis of HD and we would be interested in testing these genes in our transgenic mice. Finally, we will work with the Neuropathology Core to examine the roles of various pathological changes in the evolution of the disease in both the mice and in humans.