Abstract
Objective. To systematize current knowledge on the structural organization, conformational dynamics, and mechanisms of membrane toxicity of alpha-synuclein, as well as to analyze the role of age-associated impairment of proteostasis systems in the pathogenesis of synucleinopathies.
Material and methods. A literature review was conducted covering publications indexed in PubMed, Scopus, Web of Science, and eLibrary databases for the period 2010 – 2026.
Key Findings. Soluble prefibrillar oligomers, capable of integrating into the lipid bilayer and forming annular pores, possess the greatest damaging potential in synucleinopathies. An original hypothesis is proposed for the formation of a transmembrane pore based on the parallel stacking of NAC domains without register shifting and lateral association of subunits forming a hydrophobic interface, geometrically classified as a composite prismatoid or scutoid.
Conclusion. Understanding the molecular mechanisms of oligomer membrane toxicity and age-related proteostasis failure opens new horizons for the development of pathogenetic therapies and substantiates the implementation of highly sensitive methods for early preclinical diagnosis
Keywords
Authors and affiliations
https://elibrary.ru/wnarcj N.A. Kolotieva(1), V.V. Salmina(2), P.V. Guk(1), V.S. Voronina(1), A.V. Rossokhin(1), I.V. Salmina(3), P.P. Tregub(1), D.A. Kudlay(4, 5), S.N. Illarioshkin(1),
1Federal State Budgetary Scientific Institution “Russian Center for Neurology and Neurosciences”, Volokolamskoye Shosse, 80, Moscow, 125367, Russian Federation; 2Federal State Autonomous Educational Institution of Higher Education “Bauman Moscow State Technical University”,
2nd Baumanskaya Street, 5, build. 1, Moscow, 105005, Russian Federation; 3Federal State Autonomous Educational Institution
of Higher Education “Siberian Federal University”, Svobodny Ave., 79, Krasnoyarsk, 660041, Russian Federation; 4I.M. Sechenov
First Moscow State Medical University (Sechenov University), Trubetskaya St., 8, building 2, Moscow, 119048, Russian Federation;
5Lomonosov Moscow State University, Leninskie Gory, GSP-1, Moscow, 119991, Russian Federation
References
World Health Organization. Decade of healthy ageing: baseline report. Available from: https://www.who.int/publications/i/item/9789240017900 [Accessed 10 June, 2026].
2. Li M., Ye X., Huang Z., Ye L., Chen C. Global burden of Parkinson’s disease from 1990 to 2021: a population-based study. BMJ Open. 2025; 15 (4): e095610. DOI: 10.1136/bmjopen-2024-095610
3. Pereira Sena P., Friedrich L., Villarreal A., Fath F., Sopco L., Hernández-Guillamon M., Saraiva-Pereira M. et al. Proteostasis disruption and lipid dyshomeostasis in neurodegeneration: exploring common druggable targets across sporadic and monogenic disorders. Front. Mol. Neurosci. 2025; 18: 1681079. DOI: 10.3389/fnmol.2025.1681079
4. Bartels T., Choi J.G., Selkoe D.J. α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature. 2011; 477 (7362): 107–10. DOI: 10.1038/nature10324
5. Lashuel H.A., Petre B.M., Wall J., Simon M., Nowak R.J., Walz T., Lansbury P.T. et al. α-Synuclein, Especially the Parkinson’s Disease-associated Mutants, Forms Pore-like Annular and Tubular Protofibrils. J. Mol. Biol. 2002; 322 (5): 1089–102. DOI: 10.1016/S0022-2836(02)00735-0
6. Dhavale D.D., Barclay A.M., Borcik C.G., Basore K., Berthold D.A., Gordon I.R., Holtzman D.M. et al. Structure of alpha-synuclein fibrils derived from human Lewy body dementia tissue. Nat. Commun. 2024; 15 (1): 2750. DOI: 10.1038/s41467-024-46832-5
7. Zhou L., Kurouski D. Structural Characterization of Individual α-Synuclein Oligomers Formed at Different Stages of Protein Aggregation by Atomic Force Microscopy-Infrared Spectroscopy. Anal. Chem. 2020; 92 (10): 6806–10. DOI: 10.1021/acs.analchem.0c00593
8. Rodriguez J.A., Ivanova M.I., Sawaya M.R., Cascio D., Reyes F.E., Shi D., Sangwan S. et al. Structure of the toxic core of α-synuclein from invisible crystals. Nature. 2015; 525 (7570): 486–90. DOI: 10.1038/nature15368
9. Dutta A., Sepehri A., Lazaridis T. Putative Pore Structures of Amyloid β 25–35 in Lipid Bilayers. Biochemistry. 2023; 62 (17): 2549–58. DOI: 10.1021/acs.biochem.3c00323
10. Lashuel H.A., Hartley D., Petre B.M., Walz T., Lansbury P.T. Amyloid pores from pathogenic mutations. Nature. 2002; 418 (6895): 291. DOI: 10.1038/418291a
11. Lautenschläger J., Stephens A.D., Fusco G., Ströhl F., Curry N., Zacharopoulou M., Michel C.H. et al. C-terminal calcium binding of α-synuclein modulates synaptic vesicle interaction. Nat. Commun. 2018; 9 (1): 712. DOI: 10.1038/s41467-018-03111-4
12. Fusco G., Chen S.W., Williamson P.T.F., Cascella R., Perni M., Jarvis J.A., Dias C. et al. Structural basis of membrane disruption and cellular toxicity by α-synuclein oligomers. Science. 2017; 358 (6369): 1440–3. DOI: 10.1126/science. aan6160
13. Sant V., Matthes D., Mazal H., Antonschmidt L., Wieser F., Movellan K.T., Do D.T. et al. Lipidic folding pathway of α-Synuclein via a toxic oligomer. Nat. Commun. 2025; 16 (1): 760. DOI: 10.1038/s41467-025-55849-3
14. Maurer M., Lazaridis T. Transmembrane β-Barrel Models of α-Synuclein Oligomers. J. Chem. Inf. Model. 2023; 63 (22): 7171–9. DOI: 10.1021/acs.jcim.3c00997
15. Brøchner B.V., Malle M.G., Nielsen J., Kjems J., Otzen D.E., Zhang X. et al. Single-vesicle Tracking of α-Synuclein Oligomers Reveals Pore Formation by a Three-Stage Model. ACS Nano. 2025; 19 (36): 32108–22. DOI: 10.1021/acsnano.5c04005
16. Jang H., Zheng J., Nussinov R. Models of β-Amyloid Ion Channels in the Membrane Suggest That Channel Formation in the Bilayer Is a Dynamic Process. Biophys. J. 2007; 93 (6): 1938–49. DOI: 10.1529/biophysj.107.110148
17. Tuttle M.D., Comellas G., Nieuwkoop A.J., Covell D.J., Berthold D.A., Kloepper K.D., Courtney J.M. et al. Solid-state NMR structure of a pathogenic fibril of full-length human α-synuclein. Nat. Struct. Mol. Biol. 2016; 23 (5): 409–15. DOI: 10.1038/nsmb.3194
18. Gómez-Gálvez P., Vicente-Munuera P., Tagua A., Forja C., Castro A.M., Letrán M., Valencia-Expósito A. et al. Author Correction: Scutoids are a geometrical solution to three-dimensional packing of epithelia. Nat. Commun. 2018; 9 (1): 4210. DOI: 10.1038/s41467-018-06671-7
19. Gómez-Gálvez P., Vicente-Munuera P., Anbari S., Tagua A., Gordillo-Vázquez C., Andrés-San Román J.A., Letrán M. et al. A quantitative biophysical principle to explain the 3D cellular connectivity in curved epithelia. Cell Systems. 2022; 13 (8): 631–43. DOI: 10.1016/j.cels.2022.06.003
20. Musteikytė G., Jayaram A.K., Xu C.K., Vendruscolo M., Krainer G., Knowles T.P.J. Interactions of α-synuclein oligomers with lipid membranes. Biochim. Biophys. Acta Biomembr. 2021; 1863 (4): 183536. DOI: 10.1016/j.bbamem.2020.183536
21. Fan J., Xiang Y., Hu Q., Zhu Z., Feng S., Wu M., Gao J. et al. α-Synuclein bound to planar membrane orchestrates self-multimerization and vesicle association. Fundamental Research. 2026; S266732582600405X. DOI: 10.1016/j.fmre.2026.04.030
22. Jean D., Li Y. Synaptic Chaperone Dysfunction as a Convergent Mechanism in Neurodegenerative and Psychiatric Disorders. J. Exp. Neurosci. 2026; 21: 26331055261424760. DOI: 10.1177/26331055261424760
23. Brehme M., Voisine C., Rolland T., Wachi S., Soper J.H., Zhu Y., Isherewood K. et al. A Chaperome Subnetwork Safeguards Proteostasis in Aging and Neurodegenerative Disease. Cell Reports. 2014; 9 (3): 1135–50. DOI: 10.1016/j.celrep.2014.09.042
24. Tang Q., Gao P., Arzberger T., Höllerhage M., Herms J., Höglinger G., Levin J. et al. Alpha-Synuclein defects autophagy by impairing SNAP29-mediated autophagosome-lysosome fusion. Cell Death Dis. 2021; 12 (10): 854. DOI: 10.1038/s41419-021-04138-0
25. Yasser M.B., Hagag R.S., El-Sayed N.M., Hazem RM. Sinapic acid attenuates PERK-dependent ER stress signaling and resolves α-synuclein pathology in rotenone-induced Parkinson’s disease rat model. Neuropharmacology. 2025; 279: 110621. DOI: 10.1016/j.neuropharm.2025.110621
26. Cui H., Wang W., Zheng X., Xia D., Liu H., Qin C., Wang X. et al. Decreased AQP4 Expression Aggravates α-Synuclein Pathology in Parkinson’s Disease Mice, possibly via Impaired Glymphatic Clearance. J. Mol. Neurosci. 2021; 71 (12): 2500–13. DOI: 10.1007/s12031-021-01836-4
27. Prots I., Grosch J., Brazdis R.M., Simmnacher K., Veber V., Havlicek S., Schenk K. et al. α-Synuclein oligomers induce early axonal dysfunction in human iPSC-based models of synucleinopathies. Proc. Natl. Acad. Sci. U.S.A. 2018; 115 (30): 7813–8. DOI: 10.1073/pnas.1713129115
28. De Miranda B.R., Rocha E.M., Castro S.L., Greenamyre J.T. Protection from α-Synuclein induced dopaminergic neurodegeneration by overexpression of the mitochondrial import receptor TOM20. npj Parkinsons Dis. 2020; 6 (1): 38. DOI: 10.1038/s41531-020-00139-6
29. Fedotova E.Yu., Iakovenko E.V., Abramycheva N.Yu., Illarioshkin S.N. SNCA Gene Methylation in Parkinson’s Disease and Multiple System Atrophy. Epigenomes. 2023; 7 (1): 5. DOI: 10.3390/epigenomes7010005
30. Baek Y., Alim A., Dong Y., Olabi T., Paek J., Lee M. Lipid Acyl Chain-Driven α-Synuclein Fibril Polymorphisms and Neuronal Pathologies. ACS Chem. Neurosci. 2026; 17 (7): 1286–302. DOI: 10.1021/acschemneuro.5c00730
31. Komleva Y., Shpiliukova K., Bondar N., Salmina A., Khilazheva E., Illarioshkin S., Gorina Y. et al. Decoding brain aging trajectory: predictive discrepancies, genetic susceptibilities, and emerging therapeutic strategies. Front. Aging Neurosci. 2025; 17: 1562453. DOI: 10.3389/fnagi.2025.1562453
32. Орлова Д.А., Кудряева А.А., Колотьева Н.А., Иванова Е.О., Федотова Е.Ю., Трегуб П.П., Салмина А.Б., Иллариошкин С.Н. и др. Индуцированная конверсия мономерного α-синуклеина в реальном времени: новый подход к диагностике нейродегенеративных заболеваний из группы синуклеинопатий со слабо выраженной активностью в тесте RT-QuIC.Acta Naturae. 2025; 17 (2): 110–7. DOI: 10.32607/actanaturae.27530. [Orlova D.A., Kudryaeva A.A., Koloteva N.A., Ivanova E.O., Fedotova E.Yu., Tregub P.P., Salmina A.B., Illarioshkin S.N. et al. Induced conversion of monomeric α-synuclein in real time: a new approach to the diagnosis of neurodegenerative diseases from the group of synucleinopathies with a weakly expressed activity in the RT-QuIC test.Acta Naturae. 2025; 17 (2): 110–7. DOI: 10.32607/actanaturae.27530 (in Russian)].
33. Грошков А.А., Колотьева Н.А., Трегуб П.П., Жданкина В.И., Комлева Ю.К., Салмина А.Б., Иллариошкин С.Н. и др. Диагностика синуклеинопатий методами амплификации белков: методологический и библиометрический анализ. Биохимия. 2026; 91 (1): 1–16. [Groshkov A.A., Kolotyeva N.A., Tregub P.P., Zhdankina V.I., Komleva Y.K., Salmina A.B., Illarioshkin S.N. et al. Diagnostics of Synucleinopathies by Protein Amplification Methods: Methodological and Bibliometric Analysis. Biochemistry Moscow. 2026; 91 (1): 1–16. DOI: 10.1134/S000629792560214X (in Russian)].
34. Carlomagno C., Bertazioli D., Gualerzi A., Picciolini S., Andrico M., Rodà F., Meloni G. et al. Identification of the Raman Salivary Fingerprint of Parkinson’s Disease Through the Spectroscopic–Computational Combinatory Approach. Front. Neurosci. 2021; 15: 704963. DOI: 10.3389/fnins.2021.704963
35. Coles N.P., Elsheikh S., Gouda A., Quesnel A., Butler L., Achadu O.J., Butler L. et al. A modified α-synuclein seed amplification assay in Lewy body dementia using Raman spectroscopy and machine learning analysis. J. Neurosci. Methods. 2026; 425: 110617. DOI: 10.1016/j.jneumeth.2025.110617.