F10 Quantifying putative biomarkers of Huntington disease in blood and urine by selected reaction monitoring mass spectrometry

Background Although the gene expansion associated with Huntington Disease (HD) is well known, the downstream effects are complex and poorly understood. Delineating molecular pathways that become disrupted in the presence of an expanded repeat protein will provide insight into the relationship between the expression of proteins and underlying pathophysiology, and begin to point the way to tailored therapeutics. Aims Protein biomarkers can be sourced from bodily fluids, including blood plasma and urine, and may identify presence of disease, either before or after the appearance of signs or symptoms. The aim of the present study was to systematically profile protein expression in HD-expanded individuals, and relate these findings to metrics of disease severity. Methods We applied selected reaction monitoring (SRM) mass spectrometry (MS) proteomic profiling techniques to analyse samples from HD gene-expansion individuals that participated in PREDICT-HD. Plasma and urine samples, along with corresponding UHDRS Motor subscale scores, were supplied from 10 male HD motor manifest gene-expansion carriers (CAG repeat length >36; UHDRS Diagnostic Confidence Level >3) and 10 age-matched male controls (non-gene-expanded family members). Samples were collected as part of the PREDICT-HD protocol. Results Candidate proteins were identified to be differentially expressed in HD gene-expansion carriers relative to non-expanded familial controls. Moreover, within gene-expansion carriers, a sub-set of proteins were identified that were correlated with severity of motor manifestations, and may represent potential biomarkers of disease severity. Preliminary investigations using pooled specimens from these same patients revealed that some proteins showing differential expression in plasma appear to show similar differences in urine. Conclusions Using proteomic profiling techniques we have identified proteins showing differential expression in relation to HD, many of which to our knowledge have never before been measured in plasma. The identification of biomarkers through the use of SRM-MS holds great promise to increasing our understanding of HD.