Huntington's Disease (HD) is an autosomal dominant neurodegenerative disorder due to a mutation near the telomere of chromosome 4. Neuropathologic studies indicate a marked vulnerability of spinous Golgi II neurons in the caudate-putamen with onset of degeneration typically in mid- life. Notably, age of onset depends upon the sex of the transmitting parent. Intrastriatal injection of agonists for glutamate receptor subtypes, including NMDA, kainic acid (KA) or quisqualic acid (QA), caused a pattern of neuronal degeneration in the striatum resembling that of HD, prompting the hypothesis that endogenous glutamate causes the neuronal degeneration in HD via one of these receptors. Our research has focused on the postreceptor mechanisms responsible for QA/KA induced neuronal degeneration and has implicated oxidative stress as the proximate cause. These findings have led to trial of alpha-tocopherol and the centrally active antioxidant, idebenone, to prevent progression of HD in symptomatic individuals. In the proposed studies, we will define the pharmacologic mechanisms whereby idebenone and related drugs protect against KA striatal neurotoxicity in vivo. In addition, exploiting an in vitro model of Ca++- dependent delayed neurotoxicity due to KA, we shall determine the mechanisms of cytolysis, the role of oxidative stress, and effects of partially uncoupling mitochondrial oxidative metabolism. These studies may lead to insights into the proximate causes of HD neurodegeneration, thereby permitting pharmacologic preventive interventions.

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
United States
Zip Code
Faria, Andreia V; Ratnanather, J Tilak; Tward, Daniel J et al. (2016) Linking white matter and deep gray matter alterations in premanifest Huntington disease. Neuroimage Clin 11:450-460
Krause, Amanda; Mitchell, Claire; Essop, Fahmida et al. (2015) Junctophilin 3 (JPH3) expansion mutations causing Huntington disease like 2 (HDL2) are common in South African patients with African ancestry and a Huntington disease phenotype. Am J Med Genet B Neuropsychiatr Genet 168:573-85
Ross, Christopher A; Pantelyat, Alex; Kogan, Jane et al. (2014) Determinants of functional disability in Huntington's disease: role of cognitive and motor dysfunction. Mov Disord 29:1351-8
Hua, Jun; Unschuld, Paul G; Margolis, Russell L et al. (2014) Elevated arteriolar cerebral blood volume in prodromal Huntington's disease. Mov Disord 29:396-401
Unschuld, Paul G; Liu, Xinyang; Shanahan, Megan et al. (2013) Prefrontal executive function associated coupling relates to Huntington's disease stage. Cortex 49:2661-73
Unschuld, Paul G; Edden, Richard A E; Carass, Aaron et al. (2012) Brain metabolite alterations and cognitive dysfunction in early Huntington's disease. Mov Disord 27:895-902
Guo, Zhihong; Rudow, Gay; Pletnikova, Olga et al. (2012) Striatal neuronal loss correlates with clinical motor impairment in Huntington's disease. Mov Disord 27:1379-86
Fu, Jinrong; Jin, Jing; Cichewicz, Robert H et al. (2012) trans-(-)-?-Viniferin increases mitochondrial sirtuin 3 (SIRT3), activates AMP-activated protein kinase (AMPK), and protects cells in models of Huntington Disease. J Biol Chem 287:24460-72
Rosenblatt, Adam; Kumar, Brahma V; Mo, Alisa et al. (2012) Age, CAG repeat length, and clinical progression in Huntington's disease. Mov Disord 27:272-6
Ratovitski, Tamara; Chighladze, Ekaterine; Arbez, Nicolas et al. (2012) Huntingtin protein interactions altered by polyglutamine expansion as determined by quantitative proteomic analysis. Cell Cycle 11:2006-21

Showing the most recent 10 out of 55 publications