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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039414-04
Application #
6655658
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Oliver, Eugene J
Project Start
2000-09-01
Project End
2005-08-31
Budget Start
2003-09-01
Budget End
2005-08-31
Support Year
4
Fiscal Year
2003
Total Cost
$368,174
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Neurosciences
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Brustovetsky, N; LaFrance, R; Purl, K J et al. (2005) Age-dependent changes in the calcium sensitivity of striatal mitochondria in mouse models of Huntington's Disease. J Neurochem 93:1361-70
Brustovetsky, Tatiana; Antonsson, Bruno; Jemmerson, Ronald et al. (2005) Activation of calcium-independent phospholipase A (iPLA) in brain mitochondria and release of apoptogenic factors by BAX and truncated BID. J Neurochem 94:980-94
LaFrance, R; Brustovetsky, N; Sherburne, C et al. (2005) Age-related changes in regional brain mitochondria from Fischer 344 rats. Aging Cell 4:139-45
Brustovetsky, Tatiana; Purl, Kevin; Young, Anisa et al. (2004) Dearth of glutamate transporters contributes to striatal excitotoxicity. Exp Neurol 189:222-30
Brustovetsky, Nickolay; Brustovetsky, Tatiana; Purl, Kevin J et al. (2003) Increased susceptibility of striatal mitochondria to calcium-induced permeability transition. J Neurosci 23:4858-67
Lakkaraju, Aparna; Rahman, Yueh-Erh; Dubinsky, Janet M (2002) Low-density lipoprotein receptor-related protein mediates the endocytosis of anionic liposomes in neurons. J Biol Chem 277:15085-92