Neuronal Targets of Mutant Huntingtin Genetic Reduction to Ameliorate Huntington’s Disease Pathogenesis in Mice

Huntington’s disease (HD) is a fatal dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion leading to an elongated polyglutamine stretch in Huntingtin(1). Mutant Huntingtin (mHTT) is ubiquitously expressed but elicits selective cortical and striatal neurodegeneration in HD(2). The mechanistic basis for such selective neuronal vulnerability remains unclear. A necessary step towards resolving this enigma is to define the cell types in which mHTT expression is causally linked to the disease pathogenesis. Using a conditional human genomic transgenic mouse model of HD expressing full-length mHTT (BACHD)(3), we genetically reduced mHTT expression in striatal, cortical, or both neuronal populations. We show that cortical mHTT reduction in BACHD partially improves motor and psychiatric-like behavioral deficits, but does not improve neurodegeneration, while mHTT reduction in both neuronal populations consistently ameliorates all behavioral deficits and selective brain atrophy in this HD model. Furthermore, mHTT reduction in cortical or striatal neurons partially ameliorates cortico-striatal synaptic deficits, while further restoration of striatal synaptic function is achieved by mHTT reduction in both neuronal cell types. Our study demonstrates distinct, but interacting roles of cortical and striatal mHTT in disease pathogenesis and suggests that optimal HD therapeutics may require targeting mHTT in both cortical and striatal neurons.