Systematic Uncovering of Multiple Pathways Underlying the Pathology of Huntington Disease by an Acid-cleavable Isotope-coded

Huntington disease (HD) is an autosomal dominant neuro-degenerative disease that results from a CAG (glutamine) trinucleotide expansion in exon 1 of huntingtin (Htt). The aggregation of mutant Htt has been implicated in the pro-gression of HD. The earliest degeneration occurs in the striatum. To identify proteins critical for the progression of HD, we applied acid-cleavable ICAT technology to quanti-tatively determine changes in protein expressions in the striatum of a transgenic HD mouse model (R6/2). The cys-teine residues of striatal proteins from HD and wild-type mice were labeled, respectively, with the heavy and light forms of the ICAT reagents. Samples were trypsinized, un-covered by avidin affinity chromatography, and analyzed by nano-LC-MS/MS. Western blot analyses were used to con-firm and to calibrate the ICAT ratios. Linear regression wa