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


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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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

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.

Correspondence to X William Yang.

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Wang, N., Gray, M., Lu, X. 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) doi:10.1038/nm.3514

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