D006 Untargeted proteomics and stage-specific Huntington’s disease reveal pathways and potential protein HD-related biomarkers

<h3>Background</h3> HD is a monogenic neurodegenerative disease; its molecular manifestations remain highly complex and involve multiple cellular process. Untargeted proteomics analysis of serum proteins in varying HD stages. <h3>Aims</h3> Utilize proteomics and bioinformatics analysis to highlight the i) differentially expressed proteins (DEPs) in asymptomatic, early symptomatic, and symptomatic advanced HD stages compared to controls and ii) reveal perturbed biological pathways in the different stages of HD pathogenesis. <h3>Methods</h3> Untargeted proteomics analysis was performed with Nano Liquid-chromatography-Mass Spectrometry (LC-MC/MS) analysis, this entailed high abundant protein depletion, protein digestion, LC-MS/MS, data analysis. Bioinformatics analysis, used the IPA software for pathway and DEP identification in stage-specific HD. Biomarker candidate filter analysis was performed on the DEPs of each HD stage, the area under the curve (AUC) was performed in order to test the performance of each identified protein. Proteins with an AUC of 0.8 were considered as biomarkers of interest. Lastly, protein-protein interaction networks were constructed using DisGeNet and GWAS HD related genes using STRING. <h3>Results</h3> Pathways related to RHOGDI signaling, immune related pathways such as acute phase response signaling, complement system and cascade and LXR/RXR activation for HD. The proteins of CAP1 (AUC=0.809), in the asymptomatic HD stage. The proteins of CAPZB (AUC=0.861), LRG1 (AUC=0.828), TAGLN2 (AUC=0.886) and THBS1 (AUC=0.883) for early symptomatic HD and CFH (AUC=0.948) for the symptomatic advanced HD stage. In the PPI networks, the HTT protein interacts, SPTA1, ACTN1, ACTB, ANK1, LGALS4 that are related to cytoskeleton function and intercellular signalling and mitochondrial-related proteins, AIFM1, MAOB. <h3>Conclusion</h3> The approach in this study could potentially provide insight into the pathways and proteins affecting during the different HD stages, thereby aiding the early diagnosis of HD in asymptomatic versus early symptomatic patients. Funding: This work is supported by a grant from the European Huntington’s Disease Network (EHDN), funded by CHDI Foundation, Inc. The funding source had no role in study design, in the collection, analysis and interpretation if data; in the writing of the report; and in the decision to submit the paper for publication.