Several human neurodegenerative disorders are caused by CAG/polyglutamine repeat expansions within different genes. The preponderance of evidence suggests 'gain of function' effects at the protein level in which excessive polyglutamine tracts gain new and toxic properties. Some evidence suggests that proximate mechanisms of neurodegeneration are excitotoxic, perhaps rooted in mitochondrial dysfunction. We have developed a novel model of CAG repeat disorders by inserting a 146 unit CAG repeat disorders by inserting a 146 unit CAG repeat into the murine hypoxanthine phosphoribosyltransferase (Hprt) locus. These animals exhibit adult onset behavioral abnormalities, premature death, and neuronal intranuclear inclusions recognized recently to be characteristic of human CAG repeat diseases. Preliminary histologic analysis has not disclosed obvious neurodegeneration. A model of CAG repeat disorders that could be used to explore the pathogenesis of neurodegeneration and for preclinical intervention studies would exhibit behavior abnormalities, premature death, and neurodegeneration. We will carry out unbiased stereological analysis of neuronal density in selected brain regions in hprt/(CAG)146 mice to uncover subtle evidence of neurodegeneration. We will attempt extension of life span in HPRT-CAG mice in the hope of observing gross neurodegeneration. Neuronal intranuclear inclusions are suspected of being instrumental in causing neurodegeneration. We will correlate the development of neuronal intranuclear occlusions with the development of behavioral abnormalities and, if possible, with the development of neurodegeneration. Expanded CAG repeats may cause mitochondrial dysfunction and increased sensitivity to excitotoxic agents and mitochondrial toxins. We will use biochemical and histochemical methods to evaluate mitochondrial function in hprt(CAG)146 mice. We will determine the sensitivity of hprt/(CAG)146 mouse brains to mitochondrial toxins and excitotoxins. These experiments will establish HPRT-CAG mice as important tools for understanding neurodegeneration in CAG repeat diseases and enable accurate preclinical evaluation of interventions for CAG repeat diseases.
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