Letter | Published:

Neuronal targets for reducing mutant huntingtin expression to ameliorate disease in a mouse model of Huntington's disease

Nature Medicine volume 20, pages 536541 (2014) | Download Citation

Abstract

Huntington's disease (HD) is a fatal dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion leading to an elongated polyglutamine stretch in huntingtin1. Mutant huntingtin (mHTT) is ubiquitously expressed in all cells but elicits selective cortical and striatal neurodegeneration in HD2. The mechanistic basis for such selective neuronal vulnerability remains unclear. A necessary step toward resolving this enigma is to define the cell types in which mHTT expression is causally linked to the disease pathogenesis. Using a conditional transgenic mouse model of HD, in which the mice express full-length human mHTT from a bacterial artificial chromosome transgene (BACHD)3, we genetically reduced mHTT expression in neuronal populations in the striatum, cortex or both. We show that reduction of cortical mHTT expression in BACHD mice partially improves motor and psychiatric-like behavioral deficits but does not improve neurodegeneration, whereas reduction of mHTT expression in both neuronal populations consistently ameliorates all behavioral deficits and selective brain atrophy in this HD model. Furthermore, whereas reduction of mHTT expression in cortical or striatal neurons partially ameliorates corticostriatal synaptic deficits, further restoration of striatal synaptic function can be achieved by reduction of mHTT expression in both neuronal cell types. Our study demonstrates distinct but interacting roles of cortical and striatal mHTT in HD pathogenesis and suggests that optimal HD therapeutics may require targeting mHTT in both cortical and striatal neurons.

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Acknowledgements

X.W.Y. is supported by the US National Institutes of Health (NIH) NINDS grants R01 NS049501 and R01 NS074312, the Hereditary Disease Foundation, CHDI Foundation, Inc., Neuroscience of Brain Disorders Award from The McKnight Foundation and the David Weil Fund to the Semel Institute at University of California, Los Angeles (UCLA). X.W.Y. also receives support as the Carol Moss Spivak Scholar chair in Neuroscience from UCLA Brain Research Institute. M.S.L. is supported by NIH NINDS grant R01 NS41574. M.S.L. and C.C. are also supported by NIH grant P30 HD004612.

Author information

Author notes

    • Michelle Gray
    •  & Hongwei Dong

    Present addresses: Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama, USA (M.G.) and Laboratory of Neuro Imaging, Keck School of Medicine of the University of Southern California, University of Southern California, Los Angeles, California, USA (H.D.).

    • Nan Wang
    •  & Michelle Gray

    These authors contributed equally to this work.

Affiliations

  1. Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, California, USA.

    • Nan Wang
    • , Michelle Gray
    • , Xiao-Hong Lu
    • , Jeffrey P Cantle
    • , Erin Greiner
    • , Xiaofeng Gu
    • , Dyna Shirasaki
    •  & X William Yang
  2. Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, California, USA.

    • Nan Wang
    • , Michelle Gray
    • , Xiao-Hong Lu
    • , Jeffrey P Cantle
    • , Sandra M Holley
    • , Erin Greiner
    • , Xiaofeng Gu
    • , Dyna Shirasaki
    • , Carlos Cepeda
    • , Michael S Levine
    •  & X William Yang
  3. Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.

    • Sandra M Holley
    • , Carlos Cepeda
    •  & Michael S Levine
  4. Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, California, USA.

    • Erin Greiner
    •  & Dyna Shirasaki
  5. Department of Neurology, College of Medicine, University of Florida, Gainesville, Florida, USA.

    • Yuqing Li
  6. Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.

    • Hongwei Dong
  7. Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles, California, USA.

    • X William Yang

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Contributions

X.W.Y. provided the conceptual framework for the study, X.W.Y., N.W. and M.G. designed the experiments and discussed the results and X.W.Y. and N.W. wrote the manuscript. N.W. performed experiments shown in Figures 1b–f, 2a–g and 3a–d, Table 1, Supplementary Table 1 and Supplementary Figures 1–5. M.G. performed the experiment shown in Figure 1e, and many of the original behavioral and neuropathological studies evaluating the phenotypes of BE mice. X.-H.L. contributed to Figure 2h,i. E.G. and D.S. contributed to Figure 1e. X.G. and J.P.C. contributed to the generation of Emx1-Cre; Rgs9-Cre mice. C.C., S.M.H. and M.S.L. performed experiments shown in Figure 3e,f and Supplementary Figure 6. H.D. helped in neuroanatomical and image analyses. Y.L. provided Rgs9-Cre mice and consulted on the use of the mice.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to X William Yang.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Table 1 and Supplementary Figures 1–6

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DOI

https://doi.org/10.1038/nm.3514

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