Stage-Specific Serum Proteomic Signatures Reveal Early Biomarkers and Molecular Pathways in Huntington’s Disease Progression
Background: Huntington’s Disease (HD) is a monogenic neurodegenerative disease resulting in a CAG repeat expansion in the <i>HTT</i> gene. Despite this genetic simplicity, its molecular mechanisms remain highly complex. Methods: In this study, untargeted serum proteomics, bioinformatics...
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MDPI AG
2025-08-01
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| author | Christiana C. Christodoulou Christiana A. Demetriou Eleni Zamba-Papanicolaou |
| author_facet | Christiana C. Christodoulou Christiana A. Demetriou Eleni Zamba-Papanicolaou |
| author_sort | Christiana C. Christodoulou |
| collection | DOAJ |
| description | Background: Huntington’s Disease (HD) is a monogenic neurodegenerative disease resulting in a CAG repeat expansion in the <i>HTT</i> 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 (<i>AUC</i> = 0.809), CAPZB (<i>AUC</i> = 0.861), TAGLN2 (<i>AUC</i> = 0.886), THBS1 (<i>AUC</i> = 0.883) and CFH (<i>AUC</i> = 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. |
| format | Article |
| id | doaj-art-c59e33f91a0b4c0a905b68c21c19bb61 |
| institution | DOAJ |
| issn | 2073-4409 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | MDPI AG |
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| spelling | doaj-art-c59e33f91a0b4c0a905b68c21c19bb612025-08-20T03:02:48ZengMDPI AGCells2073-44092025-08-011415119510.3390/cells14151195Stage-Specific Serum Proteomic Signatures Reveal Early Biomarkers and Molecular Pathways in Huntington’s Disease ProgressionChristiana C. Christodoulou0Christiana A. Demetriou1Eleni Zamba-Papanicolaou2Neuroepidemiology Department, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, CyprusDepartment of Primary Care and Population Health, University of Nicosia Medical School, Nicosia 2371, CyprusNeuroepidemiology Department, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, CyprusBackground: Huntington’s Disease (HD) is a monogenic neurodegenerative disease resulting in a CAG repeat expansion in the <i>HTT</i> 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 (<i>AUC</i> = 0.809), CAPZB (<i>AUC</i> = 0.861), TAGLN2 (<i>AUC</i> = 0.886), THBS1 (<i>AUC</i> = 0.883) and CFH (<i>AUC</i> = 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.https://www.mdpi.com/2073-4409/14/15/1195Huntington’s Diseaseproteomicsserum analysisproteinsbioinformaticspathway analysis |
| spellingShingle | Christiana C. Christodoulou Christiana A. Demetriou Eleni Zamba-Papanicolaou Stage-Specific Serum Proteomic Signatures Reveal Early Biomarkers and Molecular Pathways in Huntington’s Disease Progression Cells Huntington’s Disease proteomics serum analysis proteins bioinformatics pathway analysis |
| title | Stage-Specific Serum Proteomic Signatures Reveal Early Biomarkers and Molecular Pathways in Huntington’s Disease Progression |
| title_full | Stage-Specific Serum Proteomic Signatures Reveal Early Biomarkers and Molecular Pathways in Huntington’s Disease Progression |
| title_fullStr | Stage-Specific Serum Proteomic Signatures Reveal Early Biomarkers and Molecular Pathways in Huntington’s Disease Progression |
| title_full_unstemmed | Stage-Specific Serum Proteomic Signatures Reveal Early Biomarkers and Molecular Pathways in Huntington’s Disease Progression |
| title_short | Stage-Specific Serum Proteomic Signatures Reveal Early Biomarkers and Molecular Pathways in Huntington’s Disease Progression |
| title_sort | stage specific serum proteomic signatures reveal early biomarkers and molecular pathways in huntington s disease progression |
| topic | Huntington’s Disease proteomics serum analysis proteins bioinformatics pathway analysis |
| url | https://www.mdpi.com/2073-4409/14/15/1195 |
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