# Stage-Specific Serum Proteomic Signatures Reveal Early Biomarkers and Molecular Pathways in Huntington’s Disease Progression

## TL;DR

This study identifies early blood protein markers and molecular pathways in Huntington’s Disease progression across different stages.

## Contribution

The study presents novel serum proteomic signatures and potential biomarkers specific to early Huntington’s Disease stages.

## Key findings

- 84 over-expressed and 118 under-expressed proteins were identified across Huntington’s Disease stages.
- Key biomarker proteins include CAP1, CAPZB, TAGLN2, THBS1, and CFH with high AUC values.
- Proteomic dysregulation was observed in pathways like complement cascade and LXR/RXR activation.

## Abstract

Background: Huntington’s Disease (HD) is a monogenic neurodegenerative disease resulting in a CAG repeat expansion in the HTT gene. Despite this genetic simplicity, its molecular mechanisms remain highly complex. Methods: In this study, untargeted serum proteomics, bioinformatics analysis, biomarker filtering and ELISA validation were implemented to characterize the proteomic landscape across the three HD stages—asymptomatic, early symptomatic and symptomatic advanced—alongside gender/age-matched controls. Results: We identified 84 over-expressed and 118 under-expressed differentially expressed proteins. Enrichment analysis revealed dysregulation in pathways including the complement cascade, LXR/RXR activation and RHOGDI signaling. Biomarker analysis highlighted key proteins with diagnostic potential, including CAP1 (AUC = 0.809), CAPZB (AUC = 0.861), TAGLN2 (AUC = 0.886), THBS1 (AUC = 0.883) and CFH (AUC = 0.948). CAP1 and CAPZB demonstrated robust diagnostic potential in linear mixed-effects models. CAP1 decreased in the asymptomatic stage, suggesting early cytoskeletal disruption, while CAPZB was consistently increased across HD stages. Conclusions: Our findings illuminate the dynamic proteomic and molecular landscape of HD. Future studies should validate these candidates in larger, more diverse cohorts and explore their mechanistic roles in HD pathology and progression.