Функциональная роль ганглиозидов в клеточных мембранах: от физиологии к патогенезу

Ганглиозиды — сложные гликосфинголипиды; являющиеся важнейшими компонентами клеточных мембран и активно участвующие в регуляции множества биологических процессов. Несмотря на обширные данные об их биохимических свойствах; до настоящего времени недостаточно полно изучены механизмы их участия в патогенезе различных заболеваний и возможности терапевтического воздействия. В статье рассмотрены биохимические особенности ганглиозидов; механизмы их кластеризации в мембранных микродоменах; особенности взаимодействия с белками и патогенами; а также связь нарушений их метаболизма с развитием тяжелых патологий; таких как болезнь Альцгеймера; Паркинсона; Гентинктона и боковой амиотрофический склероз. Кроме того; многие вирусы; включая SARS-CoV-2; используют ганглиозидные рецепторы для первичного контакта с клеткой. Анализируются перспективы использования ганглиозидов и их производных в качестве биомаркеров и терапевтических мишеней; обсуждаются современные подходы к направленному воздействию на ганглиозид-зависимые патологические процессы. Настоящий обзор представляет собой критический междисциплинарный анализ актуальных данных нейробиологии; иммунологии и инфекционной патологии и подчеркивает уникальную роль ганглиозидов как универсальных регуляторов клеточного ответа на различные стрессовые воздействия. Полученные выводы могут быть использованы для дальнейшего изучения молекулярных механизмов патогенеза и разработки инновационных стратегий диагностики и терапии ганглиозид-ассоциированных заболеваний.

Цель обзора. Обобщить современные представления о структуре и функциях ганглиозидов; их влиянии на клеточную активность и вовлеченности в развитие нейродегенеративных; инфекционных и аутоиммунных заболеваний.

1. Schnaar RL. The Biology of Gangliosides. Adv. Carbohydr. Chem. Biochem. 2019; 76: 113-48. doi: 10.1016/bs.accb.2018.09.002

2. Hakomori S. The Glycosynapse. Proc Natl Acad Sci U S A. 2002; 99: 225–32. doi: 10.1073/pnas.012540899

3. Aigal S, Claudinon J, Römer W. Plasma membrane reorganization: A glycolipid gateway for microbes. Biochim Biophys Acta BBA - Mol Cell Res. 2015; 1853: 858–71. doi: 10.1016/j.bbamcr.2014.11.014

4. Sipione S, Monyror J, Galleguillos D, Steinberg N, Kadam V. Gangliosides in the Brain: Physiology, Pathophysiology and Therapeutic Applications. Front Neurosci. 2020; 14: 572965. doi: 10.3389/fnins.2020.572965

5. Chiricozzi E, Lunghi G, Di Biase E, Fazzari M, Sonnino S, Mauri L. GM1 Ganglioside is a key factor in maintaining the mammalian neuronal functions avoiding neurodegeneration. Int J Mol Sci. 2020; 21: 868. doi: 10.3390/ijms21030868

6. Kabayama K, Sato T, Saito K, Loberto N, Prinetti A, Sonnino S, et al. Dissociation of the insulin receptor and caveolin-1 complex by ganglioside GM3 in the state of insulin resistance. Proc Natl Acad Sci U S A. 2007; 104: 13678–83. doi: 10.1073/pnas.0703650104

7. Seyran M, Takayama K, Uversky VN, Lundstrom K, Palù G, Sherchan SP, et al. The structural basis of accelerated host cell entry by SARS-CoV-2. FEBS J. 2021; 288: 5010-20. doi: 10.1111/febs.15651

8. Hakomori S. Glycosphingolipids in cellular interaction, differentiation, and oncogenesis. Annu Rev Biochem. 1981; 50: 733-64. doi: 10.1146/annurev.bi.50.070181.003505

9. Kusumi A, Fujiwara TK, Tsunoyama TA, Kasai RS, Liu A-A, Hirosawa KM, et al. Defining raft domains in the plasma membrane. Traffic Cph Den. 2020; 21: 106– 37. doi: 10.1111/tra.12718

10. Fantini J, Yahi N. Brain Lipids in Synaptic Function and Neurological Disease: Clues to Innovative Therapeutic Strategies for Brain Disorders. 2015. doi: 10.1016/C2013-0-09847-7

11. Iwabuchi K. Gangliosides in the Immune System: Role of Glycosphingolipids and Glycosphingolipid-Enriched Lipid Rafts in Immunological Functions. Methods Mol Biol Clifton NJ. 2018; 1804: 83–95. doi: 10.1007/978-1-4939-8552-4_4

12. Lozano MM, Liu Z, Sunnick E, Janshoff A, Kumar K, Boxer SG. Colocalization of the ganglioside G(M1) and cholesterol detected by secondary ion mass spectrometry. J Am Chem Soc. 2013; 135: 5620–30. doi: 10.1021/ja310831m

13. Boland B, Platt FM. Bridging the age spectrum of neurodegenerative storage diseases. Best Pract Res Clin Endocrinol Metab. 2015; 29: 127–43. doi: 10.1016/j.beem.2014.08.009

14. Kracun I, Kalanj S, Talan-Hranilovic J, Cosovic C. Cortical distribution of gangliosides in Alzheimer’s disease. Neurochem Int. 1992; 20: 433–8. doi: 10.1016/0197-0186(92)90058-y

15. Yanagisawa K, Odaka A, Suzuki N, Ihara Y. GM1 ganglioside-bound amyloid beta-protein (A beta): a possible form of preamyloid in Alzheimer’s disease. Nat Med. 1995; 1: 1062–6. doi: 10.1038/nm1095-1062

16. Augustinsson LE, Blennow K, Blomstrand C, Bråne G, Ekman R, Fredman P, et al. Intracerebroventricular administration of GM1 ganglioside to presenile Alzheimer patients. Dement Geriatr Cogn Disord. 1997; 8: 26–33. doi: 10.1159/000106597

17. Sonnino S. The relationship between depletion of brain GM1 ganglioside and Parkinson’s disease. FEBS Open Bio. 2023; 13: 1548–57. doi: 10.1002/2211-5463.13554

18. Hadaczek P, Wu G, Sharma N, Ciesielska A, Bankiewicz K, Davidow AL, et al. GDNF signaling implemented by GM1 ganglioside; failure in Parkinson’s disease and GM1-deficient murine model. Exp Neurol. 2015; 263: 177–89. doi: 10.1016/j.expneurol.2014.10.010

19. Fuchigami T, Itokazu Y, Morgan JC, Yu RK. Restoration of Adult Neurogenesis by Intranasal Administration of Gangliosides GD3 and GM1 in The Olfactory Bulb of A53T Alpha-Synuclein-Expressing Parkinson’s-Disease Model Mice. Mol Neurobiol. 2023; 60: 3329–44. doi: 10.1007/s12035-023-03282-2

20. Forsayeth J, Hadaczek P. Ganglioside Metabolism and Parkinson’s Disease. Front Neurosci. 2018; 12: 45. doi: 10.3389/fnins.2018.00045

21. Rapport MM, Donnenfeld H, Brunner W, Hungund B, Bartfeld H. Ganglioside patterns in amyotrophic lateral sclerosis brain regions. Ann Neurol. 1985; 18: 60–7. doi: 10.1002/ana.410180111

22. Seyfried TN, Yu RK. Cellular localization of gangliosides in the mouse cerebellum: analysis using neurological mutants. Adv Exp Med Biol. 1984; 174: 169–81. doi: 10.1007/978-1-4684-1200-0_15

23. Niebroj-Dobosz I, Jamrozik Z, Janik P, Hausmanowa-Petrusewicz I, Kwiecinski H. Anti-neural antibodies in serum and cerebrospinal fluid of amyotrophic lateral sclerosis (ALS) patients. Acta Neurol Scand. 2009; 100: 238– 43. doi: 10.1111/j.1600-0404.1999.tb00387.x

24. Desplats PA, Denny CA, Kass KE, Gilmartin T, Head SR, Sutcliffe JG, et al. Glycolipid and ganglioside metabolism imbalances in Huntington’s disease. Neurobiol Dis. 2007; 27: 265–77. doi: 10.1016/j.nbd.2007.05.003

25. Phillips GR, Saville JT, Hancock SE, Brown SHJ, Jenner AM, McLean C, et al. The long and the short of Huntington’s disease: how the sphingolipid profile is shifted in the caudate of advanced clinical cases. Brain Commun. 2022; 4: fcab303. doi: 10.1093/braincomms/fcab303

26. Alpaugh M, Galleguillos D, Forero J, Morales LC, Lackey SW, Kar P, et al. Disease-modifying effects of ganglioside GM1 in Huntington’s disease models. EMBO Mol Med. 2017; 9: 1537–57. doi: 10.15252/emmm.201707763

27. Nakayama H, Iwabuchi K. Glycosphingolipid-Enriched Lipid Rafts-Mediated Pathogen Recognition Systems. Trends Glycosci Glycotechnol. 2019; 31: E141–9. doi: 10.4052/tigg.1766.1E

28. Duan Z, He Y, Wang J, Chen X, Chen Q, Li M. Candida auris induces phagocytosis, reactive oxygen species production and inflammation through TLR2, TLR4 and Dectin-1 dependent signaling in macrophages. Int J Dermatol Venereol. 2024; 8: 1. doi: 10.21203/rs.3.rs-2765520/v1

29. Nakayama H, Kurihara H, Morita YS, Kinoshita T, Mauri L, Prinetti A, et al. Lipoarabinomannan binding to lactosylceramide in lipid rafts is essential for the phagocytosis of mycobacteria by human neutrophils. Sci Signal. 2016; 9: ra101. doi: 10.1126/scisignal.aaf1585

30. Chiricozzi E, Ciampa MG, Brasile G, Compostella F, Prinetti A, Nakayama H, et al. Direct interaction, instrumental for signaling processes, between LacCer and Lyn in the lipid rafts of neutrophil-like cells. J Lipid Res. 2015; 56: 129–41. doi: 10.1194/jlr.M055319

31. Piccardoni P, Manarini S, Federico L, Bagoly Z, Pecce R, Martelli N, et al. SRC-dependent outside-in signalling is a key step in the process of autoregulation of beta2 integrins in polymorphonuclear cells. Biochem J. 2004; 380: 57–65. doi: 10.1042/BJ20040151

32. Vetvicka V, Thornton BP, Ross GD. Soluble beta-glucan polysaccharide binding to the lectin site of neutrophil or natural killer cell complement receptor type 3 (CD11b/CD18) generates a primed state of the receptor capable of mediating cytotoxicity of iC3b-opsonized target cells. J Clin Invest. 1996; 98: 50–61. doi: 10.1172/JCI118777

33. Iwabuchi K, Nakayama H, Hanafusa K. Lactosylceramide-enriched microdomains mediate human neutrophil immunological functions via carbohydrate-carbohydrate interaction. Glycoconj J. 2022; 39: 239–46. doi: 10.1007/s10719-022-10060-0

34. Inokuchi J-I, Nagafuku M, Ohno I, Suzuki A. Distinct selectivity of gangliosides required for CD4+ T and CD8+ T cell activation. Biochim Biophys Acta. 2015; 1851: 98–106. doi: 10.1016/j.bbalip.2014.07.013

35. Saint-Ruf C, Ungewiss K, Groettrup M, Bruno L, Fehling HJ, von Boehmer H. Analysis and expression of a cloned pre-T cell receptor gene. Science. 1994; 266: 1208–12. doi: 10.1126/science.7973703

36. Yamasaki S, Saito T. Molecular basis for pre-TCR-mediated autonomous signaling. Trends Immunol. 2007; 28: 39–43. doi: 10.1016/j.it.2006.11.006

37. Bovolenta ER, García-Cuesta EM, Horndler L, Ponomarenko J, Schamel WW, Mellado M, et al. A set point in the selection of the αβTCR T cell repertoire imposed by pre-TCR signaling strength. Proc Natl Acad Sci U S A. 2022; 119: e2201907119. doi: 10.1073/pnas.2201907119

38. Kläsener K, Maity PC, Hobeika E, Yang J, Reth M. B cell activation involves nanoscale receptor reorganizations and inside-out signaling by Syk. eLife. 2014; 3: e02069. doi: 10.7554/eLife.02069

39. Minguet S, Kläsener K, Schaffer A-M, Fiala GJ, Osteso-Ibánez T, Raute K, et al. Caveolin-1-dependent nanoscale organization of the BCR regulates B cell tolerance. Nat Immunol. 2017; 18: 1150–9. doi: 10.1038/ni.3813

40. Petrov AM, Zefirov AL. Cholesterol and lipid rafts in the biological membranes. Role in the release, reception and ion channel functions. Usp Fiziol Nauk. 2013; 44: 17–38.

41. Hammache D, Yahi N, Maresca M, Piéroni G, Fantini J. Human erythrocyte glycosphingolipids as alternative cofactors for human immunodeficiency virus type 1 (HIV-1) entry: evidence for CD4-induced interactions between HIV-1 gp120 and reconstituted membrane microdomains of glycosphingolipids (Gb3 and GM3). J Virol. 1999; 73: 5244–8. doi: 10.1128/JVI.73.6.5244-5248.1999

42. Das A, Barrientos R, Shiota T, Madigan V, Misumi I, McKnight KL, et al. Gangliosides are essential endosomal receptors for quasi-enveloped and naked hepatitis A virus. Nat Microbiol. 2020; 5: 1069–78. doi: 10.1038/s41564-020-0727-8

43. Palacios-Rápalo SN, De Jesús-González LA, Cordero-Rivera CD, Farfan-Morales CN, Osuna-Ramos JF, Martínez-Mier G, et al. Cholesterol-Rich Lipid Rafts as Platforms for SARS-CoV-2 Entry. Front Immunol. 2021; 12: 796855. doi: 10.3389/fimmu.2021.796855

44. Cotton M, Phan MVT. Evolution of increased positive charge on the SARS-CoV-2 spike protein may be adaptation to human transmission. iScience. 2023; 26: 106230. doi: 10.1016/j.isci.2023.106230

45. Sviridov D, Miller YI, Ballout RA, Remaley AT, Bukrinsky M. Targeting Lipid Rafts-A Potential Therapy for COVID-19. Front Immunol. 2020; 11: 574508. doi: 10.3389/fimmu.2020.574508

46. Fantini J, Maresca M, Hammache D, Yahi N, Delézay O. Glycosphingolipid (GSL) microdomains as attachment platforms for host pathogens and their toxins on intestinal epithelial cells: activation of signal transduction pathways and perturbations of intestinal absorption and secretion. Glycoconj J. 2000; 17: 173–9. doi: 10.1023/a:1026580905156

47. Owczarek K, Szczepanski A, Milewska A, Baster Z, Rajfur Z, Sarna M, et al. Early events during human coronavirus OC43 entry to the cell. Sci Rep. 2018; 8: 7124. doi: 10.1038/s41598-018-25640-0

48. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020; 181: 271-280.e8. doi: 10.1016/j.cell.2020.02.052

49. Maguire C, Kashyap K, Williams E, Aziz R, Schuler M, Ahamed C, et al. Analysis of 977 Long COVID Patients Reveals Prevalent Neuropathy and Association with Anti-Ganglioside Antibodies. [Preprint]. 2025. doi: 10.1101/2025.03.04.25323101

50. Inci OK, Basırlı H, Can M, Yanbul S, Seyrantepe V. Gangliosides as Therapeutic Targets for Neurodegenerative Diseases. J Lipids. 2024; 2024: 4530255. doi: 10.1155/2024/4530255

51. Banerjee S, Hashemi M, Zagorski K, Lyubchenko YL. Interaction of Aβ42 with Membranes Triggers the Self-Assembly into Oligomers. Int J Mol Sci. 2020; 21: 1129. doi: 10.3390/ijms21031129

52. Schneider JS. GM1 Ganglioside as a Disease-Modifying Therapeutic for Parkinson’s Disease: A Multi-Functional Glycosphingolipid That Targets Multiple Parkinson’s Disease-Relevant Pathogenic Mechanisms. Int J Mol Sci. 2023; 24: 9183. doi: 10.3390/ijms24119183

53. Di Scala C, Armstrong N, Chahinian H, Chabrière E, Fantini J, Yahi N. AmyP53, a Therapeutic Peptide Candidate for the Treatment of Alzheimer’s and Parkinson’s Disease: Safety, Stability, Pharmacokinetics Parameters and Nose-to Brain Delivery. Int J Mol Sci. 2022; 23: 13383. doi: 10.3390/ijms232113383

54. Schneider JS, Gollomp SM, Sendek S, Colcher A, Cambi F, Du W. A randomized, controlled, delayed start trial of GM1 ganglioside in treated Parkinson’s disease patients. J Neurol Sci. 2013; 324: 140–8. doi: 10.1016/j.jns.2012.10.024

55. Halbherr S, Lerch S, Bellwald S, Polakova P, Bannert B, Roumet M, et al. Safety and tolerability of intravenous liposomal GM1 in patients with Parkinson disease: A single-center open-label clinical phase I trial (NEON trial). PLoS Med. 2025; 22: e1004472. doi: 10.1371/journal.pmed.1004472

56. Di Biase E, Lunghi G, Maggioni M, Fazzari M, Pomè DY, Loberto N, et al. GM1 Oligosaccharide Crosses the Human Blood-Brain Barrier In Vitro by a Paracellular Route. Int J Mol Sci. 2020; 21: 2858. doi: 10.3390/ijms21082858

57. Ding S, Song M, Sim B-C, Gu C, Podust VN, Wang C-W, et al. Multivalent antiviral XTEN-peptide conjugates with long in vivo half-life and enhanced solubility. Bioconjug Chem. 2014; 25: 1351–9. doi: 10.1021/bc500215m

58. Coisne C, Tilloy S, Monflier E, Wils D, Fenart L, Gosselet F. Cyclodextrins as Emerging Therapeutic Tools in the Treatment of Cholesterol-Associated Vascular and Neurodegenerative Diseases. Mol Basel Switz. 2016; 21: 1748. doi: 10.3390/molecules21121748

59. Li H, Liu Y, Wang Z, Xie Y, Yang L, Zhao Y, et al. Mass spectrometry-based ganglioside profiling provides potential insights into Alzheimer’s disease development. J Chromatogr A. 2022; 1676: 463196. doi: 10.1016/j.chroma.2022.463196