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

Nature Medicine volume 20, pages 536–541 (2014)Cite this article

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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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Figure 1: Genetic reduction of human fl-mHTT expression in neuronal populations in the cortex, striatum or both in BACHD mice.
Figure 2: Differential amelioration of behavioral deficits and selective neurodegenerative pathology in BACHD mice with genetic reduction of mHTT expression in cortical or striatal neurons.
Figure 3: Differential improvement of the levels of striatal presynaptic and postsynaptic marker proteins, as well as NMDA receptor–mediated synaptic currents in BE, BR and BER mice.

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References

  1. The Huntington's Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72, 971–983 (1993).

    Article  Google Scholar 

  2. Vonsattel, J.P. & DiFiglia, M. Huntington disease. J. Neuropathol. Exp. Neurol. 57, 369–384 (1998).

    Article  CAS  Google Scholar 

  3. Gray, M. et al. Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathogenesis in BACHD mice. J. Neurosci. 28, 6182–6195 (2008).

    Article  CAS  Google Scholar 

  4. Walker, F.O. Huntington's disease. Lancet 369, 218–228 (2007).

    Article  CAS  Google Scholar 

  5. Tabrizi, S.J. et al. Potential endpoints for clinical trials in premanifest and early Huntington's disease in the TRACK-HD study: analysis of 24 month observational data. Lancet Neurol. 11, 42–53 (2012).

    Article  Google Scholar 

  6. Kaltenbach, L.S. et al. Huntingtin interacting proteins are genetic modifiers of neurodegeneration. PLoS Genet. 11, e82 (2007).

    Article  Google Scholar 

  7. Shirasaki, D.I. et al. Network organization of the huntingtin proteomic interactome in mammalian brain. Neuron 75, 41–57 (2012).

    Article  CAS  Google Scholar 

  8. Ilieva, H., Polymenidou, M. & Cleveland, D.W. Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond. J. Cell Biol. 187, 761–772 (2009).

    Article  CAS  Google Scholar 

  9. Hadzi, T.C. et al. Assessment of cortical and striatal involvement in 523 Huntington disease brains. Neurology 79, 1708–1715 (2012).

    Article  Google Scholar 

  10. Harper, S.Q. et al. RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model. Proc. Natl. Acad. Sci. USA 102, 5820–5825 (2005).

    Article  CAS  Google Scholar 

  11. DiFiglia, M. et al. Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral deficits. Proc. Natl. Acad. Sci. USA 104, 17204–17209 (2007).

    Article  CAS  Google Scholar 

  12. Kordasiewicz, H.B. et al. Sustained therapeutic reversal of Huntington's disease by transient repression of huntingtin synthesis. Neuron 74, 1031–1044 (2012).

    Article  CAS  Google Scholar 

  13. Sah, D.W. & Aronin, N. Oligonucleotide therapeutic approaches for Huntington disease. J. Clin. Invest. 121, 500–507 (2011).

    Article  CAS  Google Scholar 

  14. Menalled, L. et al. Systematic behavioral evaluation of Huntington's disease transgenic and knock-in mouse models. Neurobiol. Dis. 35, 319–336 (2009).

    Article  CAS  Google Scholar 

  15. Gu, X. et al. Pathological cell-cell interactions elicited by a neuropathogenic form of mutant huntingtin contribute to cortical pathogenesis in HD mice. Neuron 46, 433–444 (2005).

    Article  CAS  Google Scholar 

  16. Dang, M.T. et al. Disrupted motor learning and long-term synaptic plasticity in mice lacking NMDAR1 in the striatum. Proc. Natl. Acad. Sci. USA 103, 15254–15259 (2006).

    Article  CAS  Google Scholar 

  17. Gorski, J.A. et al. Cortical excitatory neurons and glia, but not GABAergic neurons, are produced in the Emx1-expressing lineage. J. Neurosci. 22, 6309–6314 (2002).

    Article  CAS  Google Scholar 

  18. Iwasato, T. et al. Cortex-restricted disruption of NMDAR1 impairs neuronal patterns in the barrel cortex. Nature 406, 726–731 (2000).

    Article  CAS  Google Scholar 

  19. Soriano, P. Generalized lacZ expression with the Rosa26 Cre reporter strain. Nat. Genet. 21, 70–71 (1999).

    Article  CAS  Google Scholar 

  20. Madisen, L. et al. A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat. Neurosci. 13, 133–140 (2010).

    Article  CAS  Google Scholar 

  21. Schmidt, E.F. et al. Identification of the cortical neurons that mediate antidepressant responses. Cell 149, 1152–1163 (2012).

    Article  CAS  Google Scholar 

  22. Matamales, M. et al. Striatal medium-sized spiny neurons: identification by nuclear staining and study of neuronal subpopulations in BAC transgenic mice. PLoS ONE 4, e4770 (2009).

    Article  Google Scholar 

  23. Zoghbi, H.Y. & Warren, S.T. Neurogenetics: advancing the “next-generation” of brain research. Neuron 68, 165–173 (2010).

    Article  CAS  Google Scholar 

  24. Raymond, L.A. et al. Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function. Neuroscience 198, 252–273 (2011).

    Article  CAS  Google Scholar 

  25. Goto, S. & Hirano, A. Synaptophysin expression in the striatum in Huntington's disease. ActaNeuropathol. 80, 88–91 (1990).

    CAS  Google Scholar 

  26. Cepeda, C. et al. Transient and progressive electrophysiological alterations in the corticostriatal pathway in a mouse model of Huntington's disease. J. Neurosci. 23, 961–969 (2003).

    Article  CAS  Google Scholar 

  27. Kuhn, A. et al. Mutant huntingtin's effects on striatal gene expression in mice recapitulate changes observed in human Huntington's disease brain and do not differ with mutant huntingtin length or wild-type huntingtin dosage. Hum. Mol. Genet. 16, 1845–1861 (2007).

    Article  CAS  Google Scholar 

  28. Becanovic, K. et al. Transcriptional changes in Huntington disease identified using genome-wide expression profiling and cross-platform analysis. Hum. Mol. Genet. 19, 1438–1452 (2010).

    Article  CAS  Google Scholar 

  29. Wyszynski, M. et al. Competitive binding of α-actinin and calmodulin to the NMDA receptor. Nature 385, 439–442 (1997).

    Article  CAS  Google Scholar 

  30. Dunah, A.W., Wyszynski, M., Martin, D.M., Sheng, M. & Standaert, D.G. α-actinin-2 in rat striatum: localization and interaction with NMDA glutamate receptor subunits. Brain Res. Mol. Brain Res. 79, 77–87 (2000).

    Article  CAS  Google Scholar 

  31. Kennedy, M.B. The postsynaptic density at glutamatergic synapses. Trends Neurosci. 20, 264–268 (1997).

    Article  CAS  Google Scholar 

  32. Fan, J., Cowan, C.M., Zhang, L.Y., Hayden, M.R. & Raymond, L.A. Interaction of postsynaptic density protein-95 with NMDA receptors influences excitotoxicity in the yeast artificial chromosome mouse model of Huntington's disease. J. Neurosci. 29, 10928–10938 (2009).

    Article  CAS  Google Scholar 

  33. Crook, Z.R. & Housman, D. Huntington's disease: can mice lead the way to treatment? Neuron 69, 423–435 (2011).

    Article  CAS  Google Scholar 

  34. Yang, X.W., Model, P. & Heintz, N. Homologous recombination based modification in Escherichia coli and germline transmission in transgenic mice of a bacterial artificial chromosome. Nat. Biotechnol. 15, 859–865 (1997).

    Article  CAS  Google Scholar 

  35. Lobo, M.K., Karsten, S.L., Gray, M., Geschwind, D.H. & Yang, X.W. FACS-array profiling of striatal projection neuron subtypes in juvenile and adult mouse brains. Nat. Neurosci. 9, 443–452 (2006).

    Article  CAS  Google Scholar 

  36. Gu, X. et al. Serines 13 and 16 are critical determinants of full-length human mutant huntingtin induced disease pathogenesis in HD mice. Neuron 64, 828–840 (2009).

    Article  CAS  Google Scholar 

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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

  1. Michelle Gray & Hongwei Dong

    Present address: 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.).,

  2. Nan Wang and Michelle Gray: These authors contributed equally to this work.

Authors and 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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  1. Nan Wang
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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.

Corresponding author

Correspondence to X William Yang.

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The authors declare no competing financial interests.

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Supplementary Table 1 and Supplementary Figures 1–6 (PDF 704 kb)

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Wang, N., Gray, M., Lu, XH. et al. Neuronal targets for reducing mutant huntingtin expression to ameliorate disease in a mouse model of Huntington's disease. Nat Med 20, 536–541 (2014). https://doi.org/10.1038/nm.3514

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