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Ganglioside-focused Glycan Array Reveals Abnormal Anti-GD1b Auto-antibody in Plasma of Preclinical Huntington’s Disease

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Abstract

Huntington’s disease (HD) is a progressive and devastating neurodegenerative disease marked by inheritable CAG nucleotide expansion. For offspring of HD patients carrying abnormal CAG expansion, biomarkers that predict disease onset are crucially important but still lacking. Alteration of brain ganglioside patterns has been observed in the pathology of patients carrying HD. Here, by using a novel and sensitive ganglioside-focused glycan array, we examined the potential of anti-glycan auto-antibodies for HD. In this study, we collected plasma from 97 participants including 42 control (NC), 16 pre-manifest HD (pre-HD), and 39 HD cases and measured the anti-glycan auto-antibodies by a novel ganglioside-focused glycan array. The association between plasma anti-glycan auto-antibodies and disease progression was analyzed using univariate and multivariate logistic regression. The disease-predictive capacity of anti-glycan auto-antibodies was further investigated by receiver operating characteristic (ROC) analysis. We found that anti-glycan auto-antibodies were generally higher in the pre-HD group when compared to the NC and HD groups. Specifically, anti-GD1b auto-antibody demonstrated the potential for distinguishing between pre-HD and control groups. Moreover, in combination with age and the number of CAG repeat, the level of anti-GD1b antibody showed excellent predictability with an area under the ROC curve (AUC) of 0.95 to discriminate between pre-HD carriers and HD patients. With glycan array technology, this study demonstrated abnormal auto-antibody responses that showed temporal changes from pre-HD to HD.

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Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Abbreviations

AUC:

area under the ROC curve

HD:

Huntington’s disease

NC:

normal control

OR:

odds ratio

pre-HD:

pre-manifest HD

ROC:

receiver operating characteristic

References

  1. Dalrymple A, Wild EJ, Joubert R, Sathasivam K, Bjorkqvist M, Petersen A et al (2007) Proteomic profiling of plasma in Huntington’s disease reveals neuroinflammatory activation and biomarker candidates. J Proteome Res 6(7):2833–2840. https://doi.org/10.1021/pr0700753

    Article  CAS  PubMed  Google Scholar 

  2. Andrew SE, Goldberg YP, Kremer B, Telenius H, Theilmann J, Adam S et al (1993) The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington’s disease. Nat Genet 4(4):398–403. https://doi.org/10.1038/ng0893-398

    Article  CAS  PubMed  Google Scholar 

  3. Andre R, Scahill RI, Haider S, Tabrizi SJ (2014) Biomarker development for Huntington’s disease. Drug Discov Today 19(7):972–979. https://doi.org/10.1016/j.drudis.2014.03.002

    Article  CAS  PubMed  Google Scholar 

  4. Tabrizi SJ, Schobel S, Gantman EC, Mansbach A, Borowsky B, Konstantinova P et al (2022) A biological classification of Huntington’s disease: the Integrated Staging System. Lancet Neurol 21(7):632–644. https://doi.org/10.1016/S1474-4422(22)00120-X

    Article  PubMed  Google Scholar 

  5. Kinnunen KM, Schwarz AJ, Turner EC, Pustina D, Gantman EC, Gordon MF et al (2021) Volumetric MRI-based biomarkers in Huntington’s disease: an evidentiary review. Front Neurol 12:712555. https://doi.org/10.3389/fneur.2021.712555

    Article  PubMed  PubMed Central  Google Scholar 

  6. Scahill RI, Zeun P, Osborne-Crowley K, Johnson EB, Gregory S, Parker C et al (2020) Biological and clinical characteristics of gene carriers far from predicted onset in the Huntington’s disease Young Adult Study (HD-YAS): a cross-sectional analysis. Lancet Neurol 19(6):502–512. https://doi.org/10.1016/S1474-4422(20)30143-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Byrne LM, Schultz JL, Rodrigues FB, van der Plas E, Langbehn D, Nopoulos PC et al (2022) Neurofilament light protein as a potential blood biomarker for Huntington’s disease in children. Mov Disord 37(7):1526–1531. https://doi.org/10.1002/mds.29027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Yu RK, Tsai YT, Ariga T (2012) Functional roles of gangliosides in neurodevelopment: an overview of recent advances. Neurochem Res 37(6):1230–1244. https://doi.org/10.1007/s11064-012-0744-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Desplats PA, Denny CA, Kass KE, Gilmartin T, Head SR, Sutcliffe JG et al (2007) Glycolipid and ganglioside metabolism imbalances in Huntington’s disease. Neurobiol Dis 27(3):265–277. https://doi.org/10.1016/j.nbd.2007.05.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Yu RK (1994) Development regulation of ganglioside metabolism. Prog Brain Res 101:31–44

    Article  CAS  PubMed  Google Scholar 

  11. Maglione V, Marchi P, Di Pardo A, Lingrell S, Horkey M, Tidmarsh E et al (2010) Impaired ganglioside metabolism in Huntington’s disease and neuroprotective role of GM1. J Neurosci 30(11):4072–4080. https://doi.org/10.1523/JNEUROSCI.6348-09.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Pestronk A, Cornblath DR, Ilyas AA, Baba H, Quarles RH, Griffin JW et al (1988) A treatable multifocal motor neuropathy with antibodies to GM1 ganglioside. Ann Neurol 24(1):73–78. https://doi.org/10.1002/ana.410240113

    Article  CAS  PubMed  Google Scholar 

  13. Baumann N, Harpin ML, Marie Y, Lemerle K, Chassande B, Bouche P et al (1998) Antiglycolipid antibodies in motor neuropathies. Ann N Y Acad Sci 845:322–329

    Article  CAS  PubMed  Google Scholar 

  14. Sadatipour BT, Greer JM, Pender MP (1998) Increased circulating antiganglioside antibodies in primary and secondary progressive multiple sclerosis. Ann Neurol 44(6):980–983. https://doi.org/10.1002/ana.410440621

    Article  CAS  PubMed  Google Scholar 

  15. Hsu CH, Chu KC, Lin YS, Han JL, Peng YS, Ren CT et al (2010) Highly alpha-selective sialyl phosphate donors for efficient preparation of natural sialosides. Chemistry 16(6):1754–1760. https://doi.org/10.1002/chem.200903035

    Article  CAS  PubMed  Google Scholar 

  16. Chu KC, Ren CT, Lu CP, Hsu CH, Sun TH, Han JL et al (2011) Efficient and stereoselective synthesis of alpha(2-->9) oligosialic acids: from monomers to dodecamers. Angew Chem Int Ed Engl 50(40):9391–9395. https://doi.org/10.1002/anie.201101794

    Article  CAS  PubMed  Google Scholar 

  17. Wang CC, Huang YL, Ren CT, Lin CW, Hung JT, Yu JC et al (2008) Glycan microarray of Globo H and related structures for quantitative analysis of breast cancer. Proc Natl Acad Sci U S A 105(33):11661–11666. https://doi.org/10.1073/pnas.0804923105

    Article  PubMed  PubMed Central  Google Scholar 

  18. Zhang Y, Long JD, Mills JA, Warner JH, Lu W, Paulsen JS (2011) Indexing disease progression at study entry with individuals at-risk for Huntington disease. Am J Med Genet B Neuropsychiatr Genet 156b(7):751–763. https://doi.org/10.1002/ajmg.b.31232

    Article  PubMed  Google Scholar 

  19. Schmidt HB, Barreau A, Rohatgi R (2019) Phase separation-deficient TDP43 remains functional in splicing. Nat Commun 10(1):4890. https://doi.org/10.1038/s41467-019-12740-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lou YW, Wang PY, Yeh SC, Chuang PK, Li ST, Wu CY et al (2014) Stage-specific embryonic antigen-4 as a potential therapeutic target in glioblastoma multiforme and other cancers. Proc Natl Acad Sci U S A 111(7):2482–2487. https://doi.org/10.1073/pnas.1400283111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Muthana SM, Gildersleeve JC (2016) Factors affecting anti-Glycan IgG and IgM repertoires in human serum. Sci Rep 6:19509. https://doi.org/10.1038/srep19509

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hampel H, Shen Y, Walsh DM, Aisen P, Shaw LM, Zetterberg H et al (2010) Biological markers of amyloid beta-related mechanisms in Alzheimer’s disease. Exp Neurol 223(2):334–346. https://doi.org/10.1016/j.expneurol.2009.09.024

    Article  CAS  PubMed  Google Scholar 

  23. Zeun P, Scahill RI, Tabrizi SJ, Wild EJ (2019) Fluid and imaging biomarkers for Huntington’s disease. Mol Cell Neurosci 97:67–80. https://doi.org/10.1016/j.mcn.2019.02.004

    Article  CAS  PubMed  Google Scholar 

  24. Ellrichmann G, Reick C, Saft C, Linker RA (2013) The role of the immune system in Huntington’s disease. Clin Dev Immunol 2013:541259. https://doi.org/10.1155/2013/541259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Bjorkqvist M, Wild EJ, Thiele J, Silvestroni A, Andre R, Lahiri N et al (2008) A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington’s disease. J Exp Med 205(8):1869–1877. https://doi.org/10.1084/jem.20080178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. von Essen MR, Hellem MNN, Vinther-Jensen T, Ammitzboll C, Hansen RH, Hjermind LE et al (2020) Early intrathecal T helper 17.1 cell activity in Huntington disease. Ann Neurol 87(2):246–255. https://doi.org/10.1002/ana.25647

    Article  CAS  Google Scholar 

  27. Lee DH, Heidecke H, Schroder A, Paul F, Wachter R, Hoffmann R et al (2014) Increase of angiotensin II type 1 receptor auto-antibodies in Huntington’s disease. Mol Neurodegener 9:49. https://doi.org/10.1186/1750-1326-9-49

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Achenbach J, Saft C, Faissner S, Ellrichmann G (2022) Positive effect of immunomodulatory therapies on disease progression in Huntington’s disease? Data from a real-world cohort. Ther Adv Neurol Disord 15:17562864221109750. https://doi.org/10.1177/17562864221109750

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sipione S, Monyror J, Galleguillos D, Steinberg N, Kadam V (2020) Gangliosides in the brain: physiology, pathophysiology and therapeutic applications. Front Neurosci 14:572965. https://doi.org/10.3389/fnins.2020.572965

    Article  PubMed  PubMed Central  Google Scholar 

  30. Lehmann HC, Lopez PH, Zhang G, Ngyuen T, Zhang J, Kieseier BC et al (2007) Passive immunization with anti-ganglioside antibodies directly inhibits axon regeneration in an animal model. J Neurosci 27(1):27–34. https://doi.org/10.1523/JNEUROSCI.4017-06.2007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hart HS, Valentin MA, Peters ST, Holler SW, Wang H, Harmon AF et al (2022) The cytoprotective role of GM1 ganglioside in Huntington disease cells. Mol Biol Rep 49(12):12253–12258. https://doi.org/10.1007/s11033-022-07830-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Di Pardo A, Maglione V, Alpaugh M, Horkey M, Atwal RS, Sassone J et al (2012) Ganglioside GM1 induces phosphorylation of mutant huntingtin and restores normal motor behavior in Huntington disease mice. Proc Natl Acad Sci U S A 109(9):3528–3533. https://doi.org/10.1073/pnas.1114502109

    Article  PubMed  PubMed Central  Google Scholar 

  33. Alpaugh M, Galleguillos D, Forero J, Morales LC, Lackey SW, Kar P et al (2017) Disease-modifying effects of ganglioside GM1 in Huntington’s disease models. EMBO Mol Med 9(11):1537–1557. https://doi.org/10.15252/emmm.201707763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sheikh KA, Zhang G (2010) An update on pathobiologic roles of anti-glycan antibodies in Guillain-Barre syndrome. F1000 Biol Rep 2:21. https://doi.org/10.3410/B2-21

    Article  PubMed  PubMed Central  Google Scholar 

  35. Balis FM, Busch CM, Desai AV, Hibbitts E, Naranjo A, Bagatell R et al (2020) The ganglioside GD2 as a circulating tumor biomarker for neuroblastoma. Pediatr Blood Cancer 67(1):e28031. https://doi.org/10.1002/pbc.28031

    Article  CAS  PubMed  Google Scholar 

  36. Yu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman SG, Chen HX et al (2010) Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med 363(14):1324–1334. https://doi.org/10.1056/NEJMoa0911123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Drouin-Ouellet J, Sawiak SJ, Cisbani G, Lagace M, Kuan WL, Saint-Pierre M et al (2015) Cerebrovascular and blood-brain barrier impairments in Huntington’s disease: potential implications for its pathophysiology. Ann Neurol 78(2):160–177. https://doi.org/10.1002/ana.24406

    Article  PubMed  Google Scholar 

  38. Di Pardo A, Amico E, Scalabri F, Pepe G, Castaldo S, Elifani F et al (2017) Impairment of blood-brain barrier is an early event in R6/2 mouse model of Huntington Disease. Sci Rep 7:41316. https://doi.org/10.1038/srep41316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Sciacca G, Cicchetti F (2017) Mutant huntingtin protein expression and blood-spinal cord barrier dysfunction in Huntington disease. Ann Neurol 82(6):981–994. https://doi.org/10.1002/ana.25107

    Article  CAS  PubMed  Google Scholar 

  40. Huang YC, Wu YR, Tseng MY, Chen YC, Hsieh SY, Chen CM (2011) Increased prothrombin, apolipoprotein A-IV, and haptoglobin in the cerebrospinal fluid of patients with Huntington’s disease. PloS One 6(1):e15809. https://doi.org/10.1371/journal.pone.0015809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Pyo H, Joe E, Jung S, Lee SH, Jou I (1999) Gangliosides activate cultured rat brain microglia. J Biol Chem 274(49):34584–34589

    Article  CAS  PubMed  Google Scholar 

  42. Tai YF, Pavese N, Gerhard A, Tabrizi SJ, Barker RA, Brooks DJ et al (2007) Microglial activation in presymptomatic Huntington’s disease gene carriers. Brain 130(Pt 7):1759–1766. https://doi.org/10.1093/brain/awm044

    Article  PubMed  Google Scholar 

  43. Chang KH, Wu YR, Chen YC, Chen CM (2015) Plasma inflammatory biomarkers for Huntington’s disease patients and mouse model. Brain Behav Immun 44:121–127. https://doi.org/10.1016/j.bbi.2014.09.011

    Article  CAS  PubMed  Google Scholar 

  44. Di Pardo A, Alberti S, Maglione V, Amico E, Cortes EP, Elifani F et al (2013) Changes of peripheral TGF-beta1 depend on monocytes-derived macrophages in Huntington disease. Mol Brain 6:55. https://doi.org/10.1186/1756-6606-6-55

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Prof. Wen-Ping Hsieh, Inst. of Statistics, National Tsing Hua University, for consulting and analyzing initial glycan array data.

Funding

This research was supported by the Academia Sinica and Ministry of Science and Technology [MOST 106-0210-01-15-02, MOST 107-0210-01-19-01, MOST 104-2321-B-001-071] and the Chang Gung Medical Foundation [CMRPG3L141].

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Author notes

  1. Tien-Wei Lin and Jung-Kai Chang contributed equally to this work.

Authors and Affiliations

  1. Genomics Research Center, Academia Sinica, Taipei, 115, Taiwan

    Tien-Wei Lin, Jung-Kai Chang, Tsung-Hsien Sun, Yang-Yu Cheng, Chien-Tai Ren, Mei-Hung Pan, Jin-Lin Wu, Hwai-I Yang, Chung-Yi Wu & Yun-Ru Chen

  2. Department of Neurology, Linkou Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Taoyuan, Taiwan

    Yih-Ru Wu, Kuo-Hsuan Chang & Chiung-Mei Chen

  3. Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung, Taiwan

    Jin-Lin Wu

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Contributions

T.W.L performed plasma detection and related biochemical assays. J.K.C., T.H.S., Y.Y.C., and C.T.R. synthesized glycans for glycan array. T.W.L., M.H.P., and J.L.W. performed statistical analysis, Y.R.W, K.H.C., and C.M.C collected plasma samples. C.M.C. provided diagnosis and clinical aspects. H.I.Y. supervised the statistical analysis and provided statistical aspects. C.Y.W. provided and constructed glycan array technology. Y.R.C. initiated the direction and coordinated the research. T.W.L, J.L.W., H.I.Y., C.Y.W, and Y.R.C. wrote the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Chiung-Mei Chen, Chung-Yi Wu or Yun-Ru Chen.

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This study was approved by IRB in Chang Gung Memorial Hospital at Linkou and Academia Sinica (IRB01-12137).

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Lin, TW., Chang, JK., Wu, YR. et al. Ganglioside-focused Glycan Array Reveals Abnormal Anti-GD1b Auto-antibody in Plasma of Preclinical Huntington’s Disease. Mol Neurobiol 60, 3873–3882 (2023). https://doi.org/10.1007/s12035-023-03307-w

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