{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T17:22:47Z","timestamp":1784395367642,"version":"3.55.0"},"reference-count":100,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T00:00:00Z","timestamp":1754265600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Huntington\u2019s Disease Network (EHDN)","award":["1160"],"award-info":[{"award-number":["1160"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: Huntington\u2019s 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\u2014asymptomatic, early symptomatic and symptomatic advanced\u2014alongside 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.<\/jats:p>","DOI":"10.3390\/cells14151195","type":"journal-article","created":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T09:41:17Z","timestamp":1754300477000},"page":"1195","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Stage-Specific Serum Proteomic Signatures Reveal Early Biomarkers and Molecular Pathways in Huntington\u2019s Disease Progression"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6071-1715","authenticated-orcid":false,"given":"Christiana C.","family":"Christodoulou","sequence":"first","affiliation":[{"name":"Neuroepidemiology Department, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4002-2880","authenticated-orcid":false,"given":"Christiana A.","family":"Demetriou","sequence":"additional","affiliation":[{"name":"Department of Primary Care and Population Health, University of Nicosia Medical School, Nicosia 2371, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleni","family":"Zamba-Papanicolaou","sequence":"additional","affiliation":[{"name":"Neuroepidemiology Department, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Manoharan, S., Guillemin, G.J., Abiramasundari, R.S., Essa, M.M., Akbar, M., and Akbar, M.D. (2016). The Role of Reactive Oxygen Species in the Pathogenesis of Alzheimer\u2019s Disease, Parkinson\u2019s Disease, and Huntington\u2019s Disease: A Mini Review. Oxid. Med. Cell. Longev., 90578.","DOI":"10.1155\/2016\/8590578"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/1750-1172-5-40","article-title":"Huntington\u2019s Disease: A Clinical Review","volume":"5","author":"Roos","year":"2010","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1111\/cge.13168","article-title":"Epidemiology of Huntington Disease in Cyprus: A 20-Year Retrospective Study","volume":"3","author":"Demetriou","year":"2018","journal-title":"Clin. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"57","DOI":"10.4331\/wjbc.v12.i5.57","article-title":"Proteomics: Concepts and Applications in Human Medicine","volume":"12","author":"Alshekaili","year":"2021","journal-title":"World J. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1002\/pmic.201300432","article-title":"Top-down Proteomics in Health and Disease: Challenges and Opportunities","volume":"14","author":"Gregorich","year":"2014","journal-title":"Proteomics"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fmolb.2015.00054","article-title":"Molecular Diagnostics of Neurodegenerative Disorders","volume":"2","author":"Agrawal","year":"2015","journal-title":"Front. Mol. Biosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"fcac305","DOI":"10.1093\/braincomms\/fcac305","article-title":"Phosphoproteomic Dysregulation in Huntington\u2019s Disease Mice Is Rescued by Environmental Enrichment","volume":"4","author":"Mees","year":"2022","journal-title":"Brain Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3134","DOI":"10.1021\/pr070092s","article-title":"Protein Expression in the Striatum and Cortex Regions of the Brain for a Mouse Model of Huntington\u2019s Disease","volume":"6","author":"Liu","year":"2007","journal-title":"J. Proteome Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1849","DOI":"10.1074\/mcp.M500090-MCP200","article-title":"Proteomic Analysis of Protein Expression and Oxidative Modification in R6\/2 Transgenic Mice: A Model of Huntington Disease","volume":"4","author":"Perluigi","year":"2005","journal-title":"Mol. Cell. Proteom."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.brainresbull.2011.01.012","article-title":"Proteomic Changes in the Brains of Huntington\u2019s Disease Mouse Models Reflect Pathology and Implicate Mitochondrial Changes","volume":"88","author":"Deschepper","year":"2012","journal-title":"Brain Res. Bull."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Cozzolino, F., Landolfi, A., Iacobucci, I., Monaco, V., Caterino, M., Celentano, S., Zuccato, C., Cattaneo, E., and Monti, M. (2020). New Label-Free Methods for Protein Relative Quantification Applied to the Investigation of an Animal Model of Huntington Disease. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0238037"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"187","DOI":"10.3233\/JHD-150149","article-title":"Mass Spectrometry Analysis of Wild-Type and Knock-in Q140\/Q140 Huntington\u2019s Disease Mouse Brains Reveals Changes in Glycerophospholipids Including Alterations in Phosphatidic Acid and Lyso-Phosphatidic Acid","volume":"4","author":"Vodicka","year":"2015","journal-title":"J. Huntingt. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1074\/mcp.RA119.001486","article-title":"Global Proteome and Ubiquitinome Changes in the Soluble and Insoluble Fractions of Q175 Huntington Mice Brains","volume":"18","author":"Sap","year":"2019","journal-title":"Mol. Cell. Proteom."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2006","DOI":"10.4161\/cc.20423","article-title":"Huntingtin Protein Interactions Altered by Polyglutamine Expansion as Determined by Quantitative Proteomic Analysis","volume":"11","author":"Ratovitski","year":"2012","journal-title":"Cell Cycle"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"6698","DOI":"10.1007\/s12035-015-9601-8","article-title":"Induced Pluripotent Stem Cells in Huntington\u2019s Disease: Disease Modeling and the Potential for Cell-Based Therapy","volume":"53","author":"Liu","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.brainres.2015.09.020","article-title":"IPSC-Based Drug Screening for Huntingtons Disease","volume":"1638","author":"Zhang","year":"2016","journal-title":"Brain Res."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Kaye, J., Reisine, T., and Finkbeiner, S. (2022). Huntington\u2019s Disease IPSC Models\u2014Using Human Patient Cells to Understand the Pathology Caused by Expanded CAG Repeats. Fac. Rev., 11.","DOI":"10.12703\/r\/11-16"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1038\/s41467-023-36096-w","article-title":"CryoET Reveals Organelle Phenotypes in Huntington Disease Patient IPSC-Derived and Mouse Primary Neurons","volume":"14","author":"Wu","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1016\/j.celrep.2018.09.076","article-title":"Human Huntington\u2019s Disease IPSC-Derived Cortical Neurons Display Altered Transcriptomics, Morphology, and Maturation","volume":"25","author":"Mehta","year":"2018","journal-title":"Cell Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2469","DOI":"10.1093\/hmg\/ddab200","article-title":"Immortalized Striatal Precursor Neurons from Huntington\u2019s Disease Patient-Derived IPS Cells as a Platform for Target Identification and Screening for Experimental Therapeutics","volume":"30","author":"Akimov","year":"2021","journal-title":"Hum. Mol. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6066","DOI":"10.1093\/hmg\/ddv318","article-title":"Elucidating the Role of the A2A Adenosine Receptor in Neurodegeneration Using Neurons Derived from Huntington\u2019s Disease IPSCs","volume":"24","author":"Chiu","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"101743","DOI":"10.1016\/j.scr.2020.101743","article-title":"Generation of Induced Pluripotent Stem Cell Line ICGi018-A from Peripheral Blood Mononuclear Cells of a Patient with Huntington\u2019s Disease","volume":"44","author":"Malakhova","year":"2020","journal-title":"Stem Cell Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"43","DOI":"10.15283\/ijsc.2014.7.1.43","article-title":"In Vivo Roles of a Patient-Derived Induced Pluripotent Stem Cell Line (HD72-IPSC) in the YAC128 Model of Huntington\u2019s Disease","volume":"7","author":"Jeon","year":"2014","journal-title":"Int. J. Stem Cells"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3257","DOI":"10.1093\/hmg\/ddv080","article-title":"HD IPSC-Derived Neural Progenitors Accumulate in Culture and Are Susceptible to BDNF Withdrawal Due to Glutamate Toxicity","volume":"24","author":"Mattis","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Berlet, R., Galang Cabantan, D.A., Gonzales-Portillo, D., and Borlongan, C.V. (2022). Enriched Environment and Exercise Enhance Stem Cell Therapy for Stroke, Parkinson\u2019s Disease, and Huntington\u2019s Disease. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.798826"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2833","DOI":"10.1021\/pr0700753","article-title":"Proteomic Profiling of Plasma in Huntington\u2019s Disease Reveals Neuroinflammatory Activation and Biomarker Candidates","volume":"6","author":"Dalrymple","year":"2007","journal-title":"J. Proteome Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1016\/j.freeradbiomed.2008.05.014","article-title":"Proteomic and Oxidative Stress Analysis in Human Brain Samples of Huntington Disease","volume":"45","author":"Sorolla","year":"2008","journal-title":"Free Radic. Biol. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"89","DOI":"10.3233\/JHD-120044","article-title":"Proteomic Analysis of the Human Brain in Huntington\u2019s Disease Indicates Pathogenesis by Molecular Processes Linked to Other Neurodegenerative Diseases and to Type-2 Diabetes","volume":"2","author":"Jezdic","year":"2013","journal-title":"J. Huntingt. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2805","DOI":"10.1007\/s11064-012-0874-2","article-title":"Quantitative Proteomic Analysis of Human Substantia Nigra in Alzheimer\u2019s Disease, Huntington\u2019s Disease and Multiple Sclerosis","volume":"37","author":"Chen","year":"2012","journal-title":"Neurochem. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1074\/mcp.M800231-MCP200","article-title":"Brain-Specific Proteins Decline in the Cerebrospinal Fluid of Humans with Huntington Disease","volume":"8","author":"Fang","year":"2009","journal-title":"Mol. Cell. Proteom."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.pneurobio.2007.03.004","article-title":"Transcriptional Signatures in Huntington\u2019s Disease","volume":"83","author":"Cha","year":"2007","journal-title":"Prog. Neurobiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1136\/jmg.31.11.872","article-title":"Trinucleotide Repeat Length and Progression of Illness in Huntington\u2019s Disease","volume":"31","author":"Kieburtz","year":"1994","journal-title":"J. Med. Genet."},{"key":"ref_33","unstructured":"Pinheiro, J., Bates, D., DebRoy, S., Sarkar, D., Heisterkamp, S., Van Willigen, B., Ranke, J., and EISPACK (2025, May 03). R Core Team Package \u201cnlme\u201d Title Linear and Nonlinear Mixed Effects Models. Available online: https:\/\/www.google.com.hk\/url?sa=t&source=web&rct=j&opi=89978449&url=https:\/\/cran.r-project.org\/web\/packages\/nlme\/nlme.pdf&ved=2ahUKEwjpg-aSzeGOAxUOkq8BHYwUEjMQFnoECBkQAQ&usg=AOvVaw09hrCNDc-emI7xk8ixqn0Q."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1198\/jasa.2008.s216","article-title":"Linear Mixed Models: A Practical Guide Using Statistical Software","volume":"103","author":"Gilbert","year":"2008","journal-title":"J. Am. Stat. Assoc."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1001\/archpsyc.61.3.310","article-title":"Move Over ANOVA Progress in Analyzing Repeated-Measures Data and Its Reflection in Papers Published in the Archives of General Psychiatry","volume":"61","author":"Gueorguieva","year":"2004","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_36","unstructured":"Lenth, V.R., Banfai, B., Bolker, B., Buerkner, P., Iago, G.-V., Herve, M., Jung, M., Love, J., Miguez, F., and Piaskowski, J. (2025, May 05). October. Available online: https:\/\/bibbase.org\/network\/publication\/lenth-banfai-bolker-buerkner-ginvzquez-herve-jung-love-etal-emmeansestimatedmarginalmeansakaleastsquaresmeans-2024."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Korthauer, K., Kimes, P.K., Duvallet, C., Reyes, A., Subramanian, A., Teng, M., Shukla, C., Alm, E.J., and Hicks, S.C. (2019). A Practical Guide to Methods Controlling False Discoveries in Computational Biology. Genome Biol., 20.","DOI":"10.1186\/s13059-019-1716-1"},{"key":"ref_38","unstructured":"Wickham, H., Chang, W., Henry, L., Pedersen, T.L., Takahashi, K., Wilke, C., Woo, K., Yutani, H., Dunnington, D., and van den Brand, T. (2025, May 05). Create Elegant Data Visualisations Using the Grammar of Graphics. Version 3.5.1. CRAN. Available online: https:\/\/ggplot2.tidyverse.org."},{"key":"ref_39","unstructured":"Kassambara, A. (2025, May 05). ggpubr: \u2018ggplot2\u2019 Based Publication Ready Plots. R Package Version 0.6.0. Available online: https:\/\/CRAN.R-project.org\/package=ggpubr."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1686","DOI":"10.21105\/joss.01686","article-title":"Welcome to the Tidyverse","volume":"4","author":"Wickham","year":"2019","journal-title":"J. Open Source Softw."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1038\/s41467-019-09234-6","article-title":"Metascape Provides a Biologist-Oriented Resource for the Analysis of Systems-Level Datasets","volume":"10","author":"Zhou","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_42","unstructured":"Kolde, R. (2025, February 04). pheatmap: Pretty Heatmaps, Available online: https:\/\/github.com\/raivokolde\/pheatmap."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"D158","DOI":"10.1093\/nar\/gkw1099","article-title":"UniProt: The Universal Protein Knowledgebase","volume":"45","author":"Bateman","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"ClusterProfiler: An R Package for Comparing Biological Themes among Gene Clusters","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS"},{"key":"ref_45","first-page":"33","article-title":"Linear Mixed-Effects Models: Basic Concepts and Examples","volume":"Volume 96","author":"Pinheiro","year":"2000","journal-title":"Linear Mixed-Effects Models in S and S-Plus"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"bav028","DOI":"10.1093\/database\/bav028","article-title":"DisGeNET: A Discovery Platform for the Dynamical Exploration of Human Diseases and Their Genes","volume":"2015","author":"Bravo","year":"2015","journal-title":"Database"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"D977","DOI":"10.1093\/nar\/gkac1010","article-title":"The NHGRI-EBI GWAS Catalog: Knowledgebase and Deposition Resource","volume":"51","author":"Sollis","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"D605","DOI":"10.1093\/nar\/gkaa1074","article-title":"The STRING Database in 2021: Customizable Protein-Protein Networks, and Functional Characterization of User-Uploaded Gene\/Measurement Sets","volume":"49","author":"Szklarczyk","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.jns.2013.11.014","article-title":"Gene Expression Profile in Fibroblasts of Huntington\u2019s Disease Patients and Controls","volume":"337","author":"Marchina","year":"2014","journal-title":"J. Neurol. Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2788","DOI":"10.1093\/hmg\/ddaa184","article-title":"Gene Expression Profiles Complement the Analysis of Genomic Modifiers of the Clinical Onset of Huntington Disease","volume":"29","author":"Wright","year":"2020","journal-title":"Hum. Mol. Genet."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1016\/S1474-4422(17)30161-8","article-title":"Identification of Genetic Variants Associated with Huntington\u2019s Disease Progression: A Genome-Wide Association Study","volume":"16","author":"Moss","year":"2017","journal-title":"Lancet Neurol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Li, S., and Tollefsbol, T.O. (2021). DNA Methylation Methods: Global DNA Methylation and Methylomic Analyses, Elsevier Inc.","DOI":"10.1016\/j.ymeth.2020.10.002"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Neueder, A., Kojer, K., Hering, T., Lavery, D.J., Chen, J., Birth, N., Hallitsch, J., Trautmann, S., Parker, J., and Flower, M. (2022). Abnormal Molecular Signatures of Inflammation, Energy Metabolism, and Vesicle Biology in Human Huntington Disease Peripheral Tissues. Genome Biol., 23.","DOI":"10.1186\/s13059-022-02752-5"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1080\/01677063.2018.1513508","article-title":"Cortical Astroglia Undergo Transcriptomic Dysregulation in the G93A SOD1 ALS Mouse Model","volume":"32","author":"Miller","year":"2018","journal-title":"J. Neurogenet."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Seefelder, M., and Kochanek, S. (2021). A Meta-Analysis of Transcriptomic Profiles of Huntington\u2019s Disease Patients. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0253037"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/s12017-012-8183-0","article-title":"Mechanism(s) of Alteration of Micro Rna Expressions in Huntington\u2019s Disease and Their Possible Contributions to the Observed Cellular and Molecular Dysfunctions in the Disease","volume":"14","author":"Sinha","year":"2012","journal-title":"Neuromol. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1007\/s11306-016-1084-8","article-title":"Integration of Targeted Metabolomics and Transcriptomics Identifies Deregulation of Phosphatidylcholine Metabolism in Huntington\u2019s Disease Peripheral Blood Samples","volume":"12","author":"Mastrokolias","year":"2016","journal-title":"Metabolomics"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"11023","DOI":"10.1073\/pnas.0504921102","article-title":"Genome-Wide Expression Profiling of Human Blood Reveals Biomarkers for Huntington\u2019s Disease","volume":"102","author":"Borovecki","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s12987-018-0102-9","article-title":"Comparative Transcriptomics of Choroid Plexus in Alzheimer\u2019s Disease, Frontotemporal Dementia and Huntington\u2019s Disease: Implications for CSF Homeostasis","volume":"15","author":"Stopa","year":"2018","journal-title":"Fluids Barriers CNS"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"14424","DOI":"10.1073\/pnas.0703652104","article-title":"Analysis of Potential Transcriptomic Biomarkers for Huntington\u2019s Disease in Peripheral Blood","volume":"104","author":"Runne","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1002\/acn3.214","article-title":"A Systems-Level \u201cMisunderstanding\u201d: The Plasma Metabolome in Huntington\u2019s Disease","volume":"2","author":"Rosas","year":"2015","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Herman, S., Niemel\u00e4, V., Emami Khoonsari, P., Sundblom, J., Burman, J., Landtblom, A.M., Spjuth, O., Nyholm, D., and Kultima, K. (2019). Alterations in the Tyrosine and Phenylalanine Pathways Revealed by Biochemical Profiling in Cerebrospinal Fluid of Huntington\u2019s Disease Subjects. Sci. Rep., 9.","DOI":"10.1038\/s41598-019-40186-5"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"McGarry, A., Gaughan, J., Hackmyer, C., Lovett, J., Khadeer, M., Shaikh, H., Pradhan, B., Ferraro, T.N., Wainer, I.W., and Moaddel, R. (2020). Cross-Sectional Analysis of Plasma and CSF Metabolomic Markers in Huntington\u2019s Disease for Participants of Varying Functional Disability: A Pilot Study. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-77526-9"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.jnutbio.2015.12.001","article-title":"Metabolic Disturbances in Plasma as Biomarkers for Huntington\u2019s Disease","volume":"31","author":"Cheng","year":"2016","journal-title":"J. Nutr. Biochem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2430","DOI":"10.1016\/j.bbadis.2018.04.012","article-title":"Targeted Biochemical Profiling of Brain from Huntington\u2019s Disease Patients Reveals Novel Metabolic Pathways of Interest","volume":"1864","author":"Graham","year":"2018","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1016\/j.bbadis.2016.06.002","article-title":"Metabolite Mapping Reveals Severe Widespread Perturbation of Multiple Metabolic Processes in Huntington\u2019s Disease Human Brain","volume":"1862","author":"Patassini","year":"2016","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"541259","DOI":"10.1155\/2013\/541259","article-title":"The Role of the Immune System in Huntington\u2019s Disease","volume":"2013","author":"Ellrichmann","year":"2013","journal-title":"Clin. Dev. Immunol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1006\/exnr.1999.7170","article-title":"Increased Complement Biosynthesis By Microglia and Complement Activation on Neurons in Huntington\u2019s Disease","volume":"9","author":"Singhrao","year":"1999","journal-title":"Exp. Neurol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1080\/14728222.2023.2177532","article-title":"The Case for Complement Component 5 as a Target in Neurodegenerative Disease","volume":"27","author":"Stennett","year":"2023","journal-title":"Expert. Opin. Ther. Targets"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Dob\u00f3, J., Kocsis, A., Farkas, B., Demeter, F., Cervenak, L., and G\u00e1l, P. (2024). The Lectin Pathway of the Complement System\u2014Activation, Regulation, Disease Connections and Interplay with Other (Proteolytic) Systems. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25031566"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2637","DOI":"10.4049\/jimmunol.165.5.2637","article-title":"Proteolytic Activities of Two Types of Mannose-Binding Lectin-Associated Protease","volume":"5","author":"Matsushita","year":"2000","journal-title":"J. Immunol."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Massri, M., Toonen, E.J.M., Sarg, B., Kremser, L., Grasse, M., Fleischer, V., Torres-Quesada, O., Hengst, L., Skjoedt, M.O., and Bayarri-Olmos, R. (2024). Complement C7 and Clusterin Form a Complex in Circulation. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1330095"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"3483","DOI":"10.1021\/acs.analchem.6b04527","article-title":"Proteoform Profile Mapping of the Human Serum Complement Component C9 Revealing Unexpected New Features of N-, O-, and C-Glycosylation","volume":"89","author":"Franc","year":"2017","journal-title":"Anal. Chem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2866","DOI":"10.1038\/s41591-023-02566-3","article-title":"Microglia and Complement Mediate Early Corticostriatal Synapse Loss and Cognitive Dysfunction in Huntington\u2019s Disease","volume":"29","author":"Wilton","year":"2023","journal-title":"Nat. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"101314","DOI":"10.1016\/j.xcrm.2023.101314","article-title":"Complementary Insights into Corticostriatal Synapse Loss and Cognition in Huntington\u2019s Disease","volume":"4","author":"Hamilton","year":"2023","journal-title":"Cell Rep. Med."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"14554","DOI":"10.1074\/jbc.M110.165704","article-title":"Liver X Receptor-Retinoid X Receptor (LXR-RXR) Heterodimer Cistrome Reveals Coordination of LXR and AP1 Signaling in Keratinocytes","volume":"286","author":"Shen","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1016\/j.tem.2016.03.018","article-title":"LXR Regulation of Brain Cholesterol: From Development to Disease","volume":"27","author":"Courtney","year":"2016","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Paterniti, I., Campolo, M., Siracusa, R., Cordaro, M., Di Paola, R., Calabrese, V., Navarra, M., Cuzzocrea, S., and Esposito, E. (2017). Liver X Receptors Activation, through TO901317 Binding, Reduces Neuroinflammation in Parkinson\u2019s Disease. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0174470"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1007\/s12035-023-03561-y","article-title":"Role of Brain Liver X Receptor in Parkinson\u2019s Disease: Hidden Treasure and Emerging Opportunities","volume":"61","author":"Alnaaim","year":"2024","journal-title":"Mol. Neurobiol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1186\/s12974-024-03056-0","article-title":"LXR Agonism for CNS Diseases: Promises and Challenges","volume":"21","author":"Zhang","year":"2024","journal-title":"J. Neuroinflamm."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Ban, S.Y., Nam, Y., Do, T.T., Kim, B.H., Shin, S.J., Thi Nguyen, M.T., Kim, J., Moon, M., and Park, J.T. (2025). Liver-X Receptor \u03b2-Selective Agonist CE9A215 Regulates Alzheimer\u2019s Disease-Associated Pathology in a 3xTg-AD Mouse Model. Biomed. Pharmacother., 184.","DOI":"10.1016\/j.biopha.2025.117895"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"10601","DOI":"10.1073\/pnas.0701096104","article-title":"Attenuation of Neuroinflammation and Alzheimer\u2019s Disease Pathology by Liver x Receptors","volume":"104","author":"Zelcer","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1016\/j.bbalip.2014.12.018","article-title":"The Impairment of Cholesterol Metabolism in Huntington Disease","volume":"1851","author":"Leoni","year":"2015","journal-title":"Biochim. Biophys. Acta Mol. Cell Biol. Lipids"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1136\/jmg.2009.066399","article-title":"Wild-Type but Not Mutant Huntingtin Modulates the Transcriptional Activity of Liver X Receptors","volume":"46","author":"Futter","year":"2009","journal-title":"J. Med. Genet."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"449","DOI":"10.3233\/JHD-240030","article-title":"Changes in 24(S)-Hydroxycholesterol Are Associated with Cognitive Performance in Early Huntington\u2019s Disease: Data from the TRACK and ENROLL HD Cohorts","volume":"13","author":"Gray","year":"2024","journal-title":"J. Huntingt. Dis."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Mart\u00ed-Mart\u00ednez, S., and Valor, L.M. (2022). A Glimpse of Molecular Biomarkers in Huntington\u2019s Disease. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23105411"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"e717","DOI":"10.1212\/WNL.0000000000005005","article-title":"Neurofilament Light Protein in Blood Predicts Regional Atrophy in Huntington Disease","volume":"90","author":"Johnson","year":"2018","journal-title":"Neurology"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Chang, K.H., Cheng, M.L., Lo, C.J., Fan, C.M., Wu, Y.R., and Chen, C.M. (2023). Alternations of Lipoprotein Profiles in the Plasma as Biomarkers of Huntington\u2019s Disease. Cells, 12.","DOI":"10.3390\/cells12030385"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s40035-020-00215-0","article-title":"Integrated Lipidomics and Proteomics Network Analysis Highlights Lipid and Immunity Pathways Associated with Alzheimer\u2019s Disease","volume":"9","author":"Xu","year":"2020","journal-title":"Transl. Neurodegener."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1515\/hsz-2012-0103","article-title":"The Critical Role of Adrenomedullin and Its Binding Protein, AMBP-1, in Neuroprotection","volume":"393","author":"Cheyuo","year":"2012","journal-title":"Biol. Chem."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"eaba7381","DOI":"10.1126\/sciadv.aba7381","article-title":"ITIH4 Acts as a Protease Inhibitor by a Novel Inhibitory Mechanism","volume":"7","author":"Pihl","year":"2021","journal-title":"Sci. Adv."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1782","DOI":"10.1007\/s00415-013-6877-3","article-title":"ITIH4 and Gpx3 Are Potential Biomarkers for Amyotrophic Lateral Sclerosis","volume":"260","author":"Tanaka","year":"2013","journal-title":"J. Neurol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1667","DOI":"10.3233\/JAD-181218","article-title":"Acute Anti-Inflammatory Markers ITIH4 and AHSG in Mice Brain of a Novel Alzheimer\u2019s Disease Model","volume":"68","author":"Shi","year":"2019","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1042\/CS20230513","article-title":"The Complement System in Neurodegenerative Diseases","volume":"138","author":"Nimmo","year":"2024","journal-title":"Clin. Sci."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1093\/nsr\/nwy127","article-title":"Complement C7 Is a Novel Risk Gene for Alzheimer\u2019s Disease in Han Chinese","volume":"6","author":"Zhang","year":"2019","journal-title":"Natl. Sci. Rev."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Rust, M.B., and Marcello, E. (2022). Disease Association of Cyclase-Associated Protein (CAP): Lessons from Gene-Targeted Mice and Human Genetic Studies. Eur. J. Cell Biol., 101.","DOI":"10.1016\/j.ejcb.2022.151207"},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Chang, K.H., Chen, Y.C., Wu, Y.R., Lee, W.F., and Chen, C.M. (2012). Downregulation of Genes Involved in Metabolism and Oxidative Stress in the Peripheral Leukocytes of Huntington\u2019s Disease Patients. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0046492"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"55","DOI":"10.2478\/v10134-010-0008-9","article-title":"Capzb2 Protein Expression in the Brains of Patients Diagnosed with Alzheimer\u2019s Disease and Huntington\u2019s Disease","volume":"1","author":"Vanderburg","year":"2010","journal-title":"Transl. Neurosci."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Zanon Agapito-Tenfen, S., Guerra, M.P., Nodari, R.O., and Wikmark, O.G. (2021). Untargeted Proteomics-Based Approach to Investigate Unintended Changes in Genetically Modified Maize for Environmental Risk Assessment Purpose. Front. Toxicol., 3.","DOI":"10.3389\/ftox.2021.655968"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"21","DOI":"10.2174\/138920207780076910","article-title":"Challenges and Solutions in Proteomics","volume":"8","author":"Huang","year":"2007","journal-title":"Curr. Genom."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/15\/1195\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:22:35Z","timestamp":1760034155000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/15\/1195"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,4]]},"references-count":100,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["cells14151195"],"URL":"https:\/\/doi.org\/10.3390\/cells14151195","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,4]]}}}