STRIATAL ENERGETICS AND HUNTINGTON'S DISEASE

DESCRIPTION: (Adapted from the Aplicant's Abstract) Metabolic impairment is a physiological characteristic in the selective neurodegeneration associated with Huntington's disease and transgenic and knock-in mouse models of Huntington's disease. Most importantly, it is not known how the unique striatal ener aboutv deficit activated or aggravated by ubiquitous, mutant huntington expression leads to selective striatal cell death. The objective of the current proposal is to investigate the relationship between the expression of expanded CGA repeats and the bioenergetic defects associated with Huntington's disease and activation of the mitochondrial permeability transition. Our working hypothesis postulates that the metabolic impairment results in a restricted substrate supply to neuronal mitochondria. Application of exogenous metabolic inhibitors used to model Huntington's disease, e.g. 3-nitropropionic acid (3NP), would mimic this genetic defect. Under these conditions, elevations in cytosolic Ca2+, perhaps accompanying normal postsynaptic glutamate receptor activation, would cause activation of the mitochondrial permeability transition (mPT) in its low conductance state. Sustained opening of this proton permeable pathway would depolarize mitochondria, inhibit energy-dependent transhydrogenases, lowering antioxidant defenses and increasing the probability of high conductance mPT activation. Striatal neurons may be metabolically more susceptible to this sequence of events than neurons from other brain regions. Experiments are proposed to investigate key elements in this hypothesis: 1) the substrate dependence of induction of the low conductance mPT and the increased vulnerability to reactive oxygen species production, 2) antagonist sensitivity of the permeability transition in brain, 3) the ability of expanded CGA repeats and 4) 3NP to shift mitochondrial responses to Ca2+ towards low conductance mPT induction, and 5) the selective susceptibility of striatal mitochondria to this type of injury.