Huntington's disease (HD) is one of the most common inherited neurodegenerative disorders and is characterized clinically by the mid-age onset of progressive motor, cognitive and psychiatric deficits.
HD is caused by a CAG repeat expansion encoding an expanded glutamine repeat near the N-terminus of the huntingtin protein. How mutant huntingtin (mhtt) causes progressive and selective degeneration of striatal and cortical neurons, leading to symptoms of HD, remains unclear. In this presentation, I will describe a novel reductionist approach to use Cre/LoxP conditional Bacterial Artificial Chromosome (BAC) transgenic mouse models expressing full-length mhtt to dissect circuitry and molecular pathogenic mechanisms in HD.
Our study defines the distinct but synergistic roles of cortical and striatal projection neurons in HD pathogenesis, and uncovers novel evidence for HD being a non-cell-autonomous disease. Finally, we show that phosphorylation of a small mhtt N-terminus domain can act as a molecular switch to suppress HD pathogenesis in vivo.
Together, our studies provide novel mechanistic and therapeutic insights for HD.