Downloads – Striatum Disease Signature

Huntington’s disease is caused by expanded trinucleotide repeats in the huntingtin gene (HTT), and a higher number of repeats is associated with an earlier age of disease onset.  Although the causative gene has been identified, its connections to the observed disease phenotypes is still unclear.  Mouse models engineered to contain increasing numbers of trinucleotide repeats were sacrificed at different ages to detect RNA-level and protein-level changes specific to each repeat length and age in order to examine the transcriptional and translational characteristics of the disease.  RNA-seq and quantitative proteomics data were collected on 14 types of tissues at up to 8 repeat lengths and in up to 3 different ages, and differential gene and protein expression were examined.  A modified method of imputing missing proteomics data was employed and is described here.  The most dysregulated tissue at both the RNA and protein levels was the striatum, and a strong gender effect was observed in all of the liver experiments.  The full differential expression results are available to the research community on the HDinHD.org website.  The results of multiple expression tests in the striatum were combined to generate an RNA disease signature and a protein disease signature, and the signatures were validated in external data sets.  These signatures represent molecular readouts of disease progression in HD mice, which further characterizes their HD-related phenotype and can be useful in the preclinical evaluation of candidate therapeutic interventions.