Integrated Genetic and Genomic Approaches to Dissect Huntington's Disease Pathogenesis

Huntington's disease (HD) is the most common dominantly inherited neurodegenerative disorder, and is characterized by motor, cognitive, and psychiatric symptoms, as well as a relentless disease progression till death. HD is caused by a CAG repeat expansion in the Huntingtin gene, however the molecular mechanisms underlying pathogenesis of selective neurodegeneration and clinical symptoms remain poorly understood. Because HD is a monogenetic disorder, it has the advantage that all HD patients are likely to share tractable disease mechanisms, and therapeutics based on such mechanisms should benefit most, if not all HD patients. To uncover such critical disease mechanisms, our laboratory developed a series of mouse genetic models to enable stepwise dissection of cellular and molecular pathogenic mechanisms of HD in vivo. To identify molecular pathogenic mechanisms in an unbiased manner, we performed over 1000 RNA-sequencing and proteomics analyses of various brain samples from an allelic series of murine Huntingtin knockin mice expressing Huntingtin with increasing CAG repeat length. The network analyses of these rich datasets revealed novel Huntingtin CAG-length dependent gene modules, and surprising new insights into how this pathogenic network is interacting with brain aging. Finally, I will present our ongoing effort, including the use of novel mouse genetic tools, to evaluate the Huntingtin molecular network genes as modifiers of the disease.