Untargeted proteomics and stage-specific Huntington’s disease reveal biological pathways, and potential protein biomarkers

Abstract Although Huntington’s Disease is a, monogenic neurodegenerative disease, its molecular manifestations remain highly complex and involve multiple cellular process. Here, we performed untargeted proteomics analysis of serum proteins in varying stages of HD severity. Our study identified pathways related to RHOGDI signaling, immune related pathways such as acute phase response signaling, complement system and cascade and LXR/RXR activation for HD stage. Biomarker analysis revealed proteins related to cytoskeleton function and intercellular signaling such as CAP1 in asymptomatic HD patients and CAPZB in symptomatic HD patients, which were both over-expressed in these HD stages. The CFH protein is involved in complement activation and was over-expressed in symptomatic advanced HD patients. Lastly, protein-protein interaction (PPI) networks were constructed for each HD stage using HD associated genes from publicly available databases and the differently expressed proteins for each HD stage. The HTT protein interacts with proteins, SPTA1, ACTN1, ACTB, ANK1, LGALS4 that are related to cytoskeleton function and intercellular signalling, mitochondrial related proteins such as AIFM1, MAOB. Therefore, it is essential to investigate the biological mechanisms, protein interactions and potential biomarkers for each HD stage, as this will lead to a better understanding of the disease and open the way for potential treatment.