Genetic Suppressors of Huntington's Disease in Mice

Summary

Principal Investigator: Xiangdong Yang
Abstract: Huntington's disease (HD) is a devastating neurodegenerative disease caused by a polyglutamine expansion mutation in the Huntingtin gene (Ht). The mutant Huntingtin (mHt) exerts dominant toxicity to cause selective neuronal dysfunction and degeneration. Currently, there are very few valid drug targets for HD. One method to identify new drug targets is through genetic modifier studies. Genetic = modifier screenings in Yeast, Drosophila, C. elegans and mammalian cell culture have produced a number of genes that can be manipulated to suppress mutant Huntingtin toxicity. However, the efficacy of these genes to suppress mutant Huntingtin toxicity in the mammalian brain is unclear. This proposal seeks to establish a mouse genetic system that can readily and systematically test genetic suppressors for HD in vivo. Using a relatively novel mouse genetic technology, called Bacterial Artificial Chromosome (BAC) mediated transgenics, we have succeeded in creating novel transgenic mouse models of HI) expressing full-length mutant Huntingtin under the endogenous regulation. Some of these full-length transgenic founders have already demonstrated early and severe motor deficits. The specific aims of this proposal are to: 1. Characterize the fulfull-lengthC models of HD and select lines suitable for genetic modifier studies. 2. Apply the newly developed rapid BAC modification system to generate mice over expressing two modifier genes and to test their efficacy in suppressing mHt toxicity in the full-length transgenic models. If proven effective, our BAC transgenic System can readily be scaled up to systematically study a large number of putative HD genetic modifiers in vivo. Identification of effective genetic modifiers in mice may provide novel insights into disease pathogenesis and new targets to develop therapeutics.
Funding Period: 2004-06-01 - 2006-05-31
more information: NIH RePORT

Top Publications

  1. ncbi FACS-array profiling of striatal projection neuron subtypes in juvenile and adult mouse brains
    Mary Kay Lobo
    Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, 90095, USA
    Nat Neurosci 9:443-52. 2006
  2. pmc Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathogenesis in BACHD mice
    Michelle Gray
    Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, California 90095, USA
    J Neurosci 28:6182-95. 2008
  3. pmc Progressive synaptic pathology of motor cortical neurons in a BAC transgenic mouse model of Huntington's disease
    J Spampanato
    Department of Neurology, David Geffen School of Medicine, University of California, NRB1 Room 575D, 635 Charles E Young Drive South, Los Angeles, CA 90095 7335, USA
    Neuroscience 157:606-20. 2008

Detail Information

Publications3

  1. ncbi FACS-array profiling of striatal projection neuron subtypes in juvenile and adult mouse brains
    Mary Kay Lobo
    Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, 90095, USA
    Nat Neurosci 9:443-52. 2006
    ..Our study provides a general approach for profiling cell type-specific gene expression in the mature mammalian brain and identifies a set of genes critical to the function and dysfunction of the striatal projection neuron circuit...
  2. pmc Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathogenesis in BACHD mice
    Michelle Gray
    Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, California 90095, USA
    J Neurosci 28:6182-95. 2008
    ..In summary, the BACHD model constitutes a novel and robust in vivo paradigm for the investigation of HD pathogenesis and treatment...
  3. pmc Progressive synaptic pathology of motor cortical neurons in a BAC transgenic mouse model of Huntington's disease
    J Spampanato
    Department of Neurology, David Geffen School of Medicine, University of California, NRB1 Room 575D, 635 Charles E Young Drive South, Los Angeles, CA 90095 7335, USA
    Neuroscience 157:606-20. 2008
    ..The synaptic pathology occurs prior to neuronal degeneration and may therefore prove useful as a target for future therapeutic design...