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Huntingtin inclusions do not down-regulate specific genes in the R6/2 Huntington's disease mouse

Authors

  • G. Sadri-Vakili,

    1. Massachusetts General Hospital, MassGeneral Institute for Neurodegenerative Disease, 114 16th Street/B114- 2001, Charlestown, MA 02129-4404, USA
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  • A. S. Menon,

    1. Massachusetts General Hospital, MassGeneral Institute for Neurodegenerative Disease, 114 16th Street/B114- 2001, Charlestown, MA 02129-4404, USA
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  • L. A. Farrell,

    1. Massachusetts General Hospital, MassGeneral Institute for Neurodegenerative Disease, 114 16th Street/B114- 2001, Charlestown, MA 02129-4404, USA
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  • C. E. Keller-McGandy,

    1. Massachusetts General Hospital, MassGeneral Institute for Neurodegenerative Disease, 114 16th Street/B114- 2001, Charlestown, MA 02129-4404, USA
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  • I. Cantuti-Castelvetri,

    1. Massachusetts General Hospital, MassGeneral Institute for Neurodegenerative Disease, 114 16th Street/B114- 2001, Charlestown, MA 02129-4404, USA
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  • D. G. Standaert,

    1. Massachusetts General Hospital, MassGeneral Institute for Neurodegenerative Disease, 114 16th Street/B114- 2001, Charlestown, MA 02129-4404, USA
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  • S. J. Augood,

    1. Massachusetts General Hospital, MassGeneral Institute for Neurodegenerative Disease, 114 16th Street/B114- 2001, Charlestown, MA 02129-4404, USA
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  • G. J. Yohrling,

    1. Johnson & Johnson Pharmaceuticals, Research & Development, L.L.C., Welsh & McKean Roads, PO Box 776, Spring House, PA 19477-0776, USA
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  • J.-H. J. Cha

    1. Massachusetts General Hospital, MassGeneral Institute for Neurodegenerative Disease, 114 16th Street/B114- 2001, Charlestown, MA 02129-4404, USA
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Dr J-H. J. Cha, as above.
E-mail: cha@helix.mgh.harvard.edu

Abstract

Transcriptional dysregulation is a central pathogenic mechanism in Huntington's disease (HD); HD and transgenic mouse models of HD demonstrate down-regulation of specific genes at the level of mRNA expression. Furthermore, neuronal intranuclear inclusions (NIIs) have been identified in the brains of R6/2 mice and HD patients. One possibility is that NIIs contribute to transcriptional dysregulation by sequestering transcription factors. We therefore assessed the relationship between NIIs and transcriptional dysregulation in the R6/2 mouse, using double-label in situ hybridization combined with immunohistochemistry, and laser capture microdissection combined with quantitative real-time PCR. There was no difference in transcript levels of specific genes between NII-positive and NII-negative neurons. These results demonstrate that NIIs do not cause decreases in D2, PPE and PSS mRNA levels in R6/2 striatum and therefore are not involved in the down-regulation of these specific genes in this HD model. In addition, these observations argue against the notion that NIIs protect against transcriptional dysregulation in HD.

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