Due to unprecedented increases in the elderly populations, age-related diseases are expected to increase exponentially in the coming years. Among these, neurodegenerative diseases will be the most devastating in terms of their emotional and economic effects. In the next decade, at least 2% of Americans will be afflicted with some form of Alzheimer's disease (AD) (4,000,000), Parkinson's disease (PD) (1,500,000), or Huntington's disease (HD) (200,000), among others. Each of these disorders can affect patients for decades, yet no effective long-term approaches to therapy are currently available. In this proposal, we aim to test mechanisms that prevent or delay onset of and progression of HD. We have surprisingly found that a DNA oxidative damage causes the somatic expansion in Huntington's Disease that is observed with age and governs onset that begins around mid-life. Loss of a single base excision repair enzyme, 8-oxo-guanine glycosylase (OGG1), in hHD/OGG1(-/-) mice stops age-dependent expansion of CAG triplet repeats that is observed in mhtt mice. A second surprise was that loss of expansion was accompanied by an unforeseen amelioration (or at least a substantial delay) of pathophysiology. Animals expressing hHD protein but lacking OGG1 appeared devoid of visible signs of disease typically observed late in the lifetime of these animals. These data demonstrate, for the first time, the unexpected finding that oxidation of DNA bases and/or their removal are causative factors in both DNA expansion and the onset of toxicity. Our discovery that loss of OGG1 stops expansion provides a direct molecular link between oxidative DNA damage and the mechanism of expansion, and onset of pathophysiology. We have created a new HD mouse model in which an mhttexpressing animal of 150 repeats (HD150KI) is crossed with an animals lacking OGG1(-/-) producing (HD150KI/OGG1(-/-)) progeny. HD150KI animals display a neurological phenotype, transmit an expanded allele, and expand the inherited allele in somatic tissues with age. In contrast, HD150KI/OGG1(-/-) animals can inherit the CAG repeat but cannot expand their repeats in somatic brain cells. Both mice express mhtt. Since, the OGG1(-/-) animals have no observable neurological phenotype on their own, the HD150 KI/OGG1(-/-) mice will allow us to test whether loss of somatic expansion alters disease onset relative to their mhtt-expressing counterparts (HD150KI). Our model predicts that suppressing somatic expansion will offset or delay the onset of motor dysfunction and other measures of disease pathophysiology in HD150 KI/OGG1(-/-) mice relative to HD150KI animals. We will also test whether OGG1 activity is the source of both the somatic expansion and rise in the peripheral biomarkers associated with disease onset. We will test whether reduction in somatic expansion observed in HD150 KI/OGG1(-/-) mice is accompanied by reduction in the biomarker relative to HD150KI animals. In a reverse approach, we will reduce biomarker production in HD150KI mice by treatment with anti-oxidants, and test whether somatic expansion is also reduced.

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National Institute of Neurological Disorders and Stroke (NINDS)
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Neural Oxidative Metabolism and Death Study Section (NOMD)
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Sutherland, Margaret L
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Lawrence Berkeley National Laboratory
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Trushina, Eugenia; Canaria, Christie A; Lee, Do-Yup et al. (2014) Loss of caveolin-1 expression in knock-in mouse model of Huntington's disease suppresses pathophysiology in vivo. Hum Mol Genet 23:129-44
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Lee, Do Yup; Xun, Zhiyin; Platt, Virginia et al. (2013) Distinct pools of non-glycolytic substrates differentiate brain regions and prime region-specific responses of mitochondria. PLoS One 8:e68831
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Budworth, Helen; McMurray, Cynthia T (2013) A brief history of triplet repeat diseases. Methods Mol Biol 1010:3-17
Xun, Zhiyin; Rivera-Sánchez, Sulay; Ayala-Peña, Sylvette et al. (2012) Targeting of XJB-5-131 to mitochondria suppresses oxidative DNA damage and motor decline in a mouse model of Huntington's disease. Cell Rep 2:1137-42
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Lee, Do Yup; Platt, Virginia; Bowen, Ben et al. (2012) Resolving brain regions using nanostructure initiator mass spectrometry imaging of phospholipids. Integr Biol (Camb) 4:693-9
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Kovtun, Irina V; Johnson, Kurt O; McMurray, Cynthia T (2011) Cockayne syndrome B protein antagonizes OGG1 in modulating CAG repeat length in vivo. Aging (Albany NY) 3:509-14

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