THE X. WILLIAM YANG RESEARCH GROUP @ UCLA

Since mutant Huntingtin (mhtt) is widely expressed, but neuronal degeneration in HD is very selective, one key but unresolved question in HD is whether mhtt cause selective toxicity purely due its toxicities within the vulnerable neurons (cell-autonomous toxicities) or due to pathological cell-cell interactions. Resolving this question will help to identify novel cellular and molecular targets to treat HD.

To study this question, we have developed a Cre/LoxP conditional mouse model of HD. In this model, expression of a neuropathogenic fragment of mhtt (mhtt-exon 1), driven by the Rosa26 promoter, can be activated in specific neuronal types by crossing with cell-type-specific Cre mouse lines. Using this system, we specifically turned on mhtt expression in all the neurons in the brain (pan-neuronal model) or only in the cortical pyramidal neurons, one of the neuronal type that degenerate in HD. We show that mhtt aggregation is a cell-autonomous process. However, progressive motor deficits and cortical neuropathology are only observed when mhtt expression is in multiple neuronal types, but not when mhtt expression is restricted to cortical pyramidal neurons. We further demonstrate an early deficit in cortical inhibition, suggesting that pathological interactions between interneurons and pyramidal neurons may contribute to the cortical manifestation of HD. Our study provides the first genetic evidence that pathological cell-cell interactions elicited by neuropathogenic forms of mHtt can critically contribute to cortical pathogenesis in HD.

Currently, we are focusing on studying whether pathological cell-cell interactions are also required for striatal pathogenesis in HD, and whether turning off mhtt expression in specific neuronal types can eliminate such interactions and reduce HD phenotypes in vivo.

Pathological Cell-Cell Interactions in Huntington Disease Mice

Description of the Image:
Expanded polyglutamine (polyQ) proteins in Huntington’s disease (HD) as well as in other polyQ disorders can elicit a variety of intracellular toxicities that may contribute to neurodegeneration. An alternative but less explored pathogenic mechanism postulates that polyQ proteins may generate pathological cell-cell interactions which are critical to disease pathogenesis. Using a conditional mouse model of HD, Gu et al provide the first genetic evidence to demonstrate that pathological cell-cell interactions are critical to cortical pathogenesis in vivo. This is an EM photo of the HD mouse cortex demonstrating three dark degenerating neurons, and an illustration of a cortical local circuitry consisting of an inhibitory interneuron and a pyramidal neuron. The drawing highlights the pathological interactions between these two types of neurons may contribute to early cortical manifestation of HD in mice. The black dots in the nuclei of the two neurons represent aggregated mutant Huntingtin. EM photo provided by Xian-Jiang Li and illustration created by Xiaohong Lu.