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Innovative treatment targeting gangliosides aimed at blocking the formation of neurotoxic α-synuclein oligomers in Parkinson’s disease

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Abstract

Parkinson’s disease (PD) is a major neurodegenerative disorder which exhibits many of the characteristics of a pandemic. Current therapeutic strategies are centered on the dopaminergic system, with limited efficacy, so that a treatment that has a direct impact on the underlying disease pathogenesis is urgently needed. Although α-synuclein is a privileged target for such therapies, this protein has been in the past wrongly considered as exclusively intracellular, so that the impact of paracrine neurotoxicity mechanisms in PD have been largely ignored. In this article we review the data showing that lipid rafts act as plasma membrane machineries for the formation of α-synuclein pore-like oligomers which trigger an increase of intracellular Ca2+. This Ca2+ influx is responsible for a self-sustained cascade of neurotoxic events, including mitochondrial oxidative stress, tau phosphorylation, Ca2+ release from the endoplasmic reticulum, Lewy body formation, and extracellular release of α-synuclein in exosomes. The first step of this cascade is the binding of α-synuclein to lipid raft gangliosides, suggesting that PD should be considered as both a proteinopathy and a ganglioside membrane disorder lipidopathy. Accordingly, blocking α-synuclein-ganglioside interactions should annihilate the whole neurotoxic cascade and stop disease progression. A pipeline of anti-oligomer molecules is under development, among which an in-silico designed synthetic peptide AmyP53 which is the first drug targeting gangliosides and thus able to prevent the formation of α-synuclein oligomers and all downstream neurotoxicity. These new therapeutic avenues challenge the current symptomatic approaches by finally targeting the root cause of PD through a long-awaited paradigm shift.

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References

  1. Dorsey, E.R., Bloem, B.R.: The Parkinson Pandemic-A Call to Action. JAMA Neurol. 75, 9–10 (2018)

    Article  PubMed  Google Scholar 

  2. GBD 2016 Parkinson's Disease Collaborators.: Global, regional, and national burden of Parkinson's disease, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. Neurol. 17, 939-953 (2018)

  3. Charvin, D., Medori, R., Hauser, R.A., Rascol, O.: Therapeutic strategies for Parkinson disease: beyond dopaminergic drugs. Nat. Rev. Drug. Discov. 17, 844 (2018)

    Article  CAS  PubMed  Google Scholar 

  4. Jao, C.C., Hegde, B.G., Chen, J., Haworth, I.S., Langen, R.: Structure of membrane-bound alpha-synuclein from site-directed spin labeling and computational refinement. Proc. Natl. Acad. Sci. U. S. A. 105, 19666–19671 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Rawat, A., Langen, R., Varkey, J.: Membranes as modulators of amyloid protein misfolding and target of toxicity. Biochim. Biophys. Acta Biomembr. 1860, 1863–1875 (2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Murphy, D.D., Rueter, S.M., Trojanowski, J.Q., Lee, V.M.: Synucleins are developmentally expressed, and alpha-synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons. J. Neurosci. 20, 3214–3220 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Nemani, V.M., Lu, W., Berge, V., Nakamura, K., Onoa, B., Lee, M.K., Chaudhry, F.A., Nicoll, R.A., Edwards, R.H.: Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron 65, 66–79 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Golovko, M.Y., Barceló-Coblijn, G., Castagnet, P.I., Austin, S., Combs, C.K., Murphy, E.J.: The role of alpha-synuclein in brain lipid metabolism: a downstream impact on brain inflammatory response. Mol. Cell. Biochem. 326, 55–66 (2009)

    Article  CAS  PubMed  Google Scholar 

  9. Bendor, J.T., Logan, T.P., Edwards, R.H.: The function of α-synuclein. Neuron 79, 1044–1066 (2013)

    Article  CAS  PubMed  Google Scholar 

  10. Winner, B., Jappelli, R., Maji, S.K., Desplats, P.A., Boyer, L., Aigner, S., Hetzer, C., Loher, T., Vilar, M., Campioni, S., et al.: In vivo demonstration that alpha-synuclein oligomers are toxic. Proc. Natl. Acad. Sci. U. S. A. 108, 4194–4199 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Paleologou, K.E., Kragh, C.L., Mann, D.M., Salem, S.A., Al-Shami, R., Allsop, D., Hassan, A.H., Jensen, P.H., El-Agnaf, O.M.: Detection of elevated levels of soluble alpha-synuclein oligomers in post-mortem brain extracts from patients with dementia with Lewy bodies. Brain 132, 1093–1101 (2009)

    Article  PubMed  Google Scholar 

  12. El-Agnaf, O.M., Salem, S.A., Paleologou, K.E., Curran, M.D., Gibson, M.J., Court, J.A., Schlossmacher, M.G., Allsop, D.: Detection of oligomeric forms of alpha-synuclein protein in human plasma as a potential biomarker for Parkinson’s disease. FASEB J. 20, 419–425 (2006)

    Article  CAS  PubMed  Google Scholar 

  13. Park, M.J., Cheon, S.M., Bae, H.R., Kim, S.H., Kim, J.W.: Elevated levels of α-synuclein oligomer in the cerebrospinal fluid of drug-naïve patients with Parkinson’s disease. J. Clin. Neurol. 7, 215–222 (2011)

    Article  PubMed  PubMed Central  Google Scholar 

  14. Lee, H.J., Patel, S., Lee, S.J.: Intravesicular localization and exocytosis of alpha-synuclein and its aggregates. J. Neurosci. 25, 6016–6024 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Vekrellis, K., Stefanis, L.: Targeting intracellular and extracellular alpha-synuclein as a therapeutic strategy in Parkinson’s disease and other synucleinopathies. Expert Opin. Ther. Targets 16, 421–432 (2012)

    Article  CAS  PubMed  Google Scholar 

  16. Emmanouilidou, E., Vekrellis, K.: Exocytosis and Spreading of Normal and Aberrant α-Synuclein. Brain Pathol. 26, 398–403 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Emmanouilidou, E., Elenis, D., Papasilekas, T., Stranjalis, G., Gerozissis, K., Ioannou, P.C., Vekrellis, K.: Assessment of α-synuclein secretion in mouse and human brain parenchyma. PLoS One 6, e22225 (2011)

  18. Danzer, K.M., Ruf, W.P., Putcha, P., Joyner, D., Hashimoto, T., Glabe, C., Hyman, B.T., McLean, P.J.: Heat-shock protein 70 modulates toxic extracellular α-synuclein oligomers and rescues trans-synaptic toxicity. FASEB J. 25, 326–336 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sui, Y.T., Bullock, K.M., Erickson, M.A., Zhang, J., Banks, W.A.: Alpha synuclein is transported into and out of the brain by the blood-brain barrier. Peptides 62, 197–202 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gray, M.T., Woulfe, J.M.: Striatal blood-brain barrier permeability in Parkinson’s disease. J. Cereb. Blood Flow Metab. 35, 747–750 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Trudler, D., Nazor, K.L., Eisele, Y.S., Grabauskas, T., Dolatabadi, N., Parker, J., Sultan, A., Zhong, Z., Goodwin, M.S., Levites, Y., et al.: Soluble α-synuclein-antibody complexes activate the NLRP3 inflammasome in hiPSC-derived microglia. Proc. Natl. Acad. Sci. U. S. A. 118, (2021)

  22. Valdinocci, D., Radford, R.A., Siow, S.M., Chung, R.S., Pountney, D.L.: Potential modes of intercellular α-synuclein transmission. Int. J. Mol. Sci. 18, (2017)

  23. Pacheco, C.R., Morales, C.N., Ramírez, A.E., Muñoz, F.J., Gallegos, S.S., Caviedes, P.A., Aguayo, L.G., Opazo, C.M.: Extracellular α-synuclein alters synaptic transmission in brain neurons by perforating the neuronal plasma membrane. J. Neurochem. 132, 731–741 (2015)

    Article  CAS  PubMed  Google Scholar 

  24. Koziorowski, D., Figura, M., Milanowski, Ł.M., Szlufik, S., Alster, P., Madetko, N., Friedman, A.: Mechanisms of neurodegeneration in various forms of Parkinsonism-similarities and differences. Cells 10, (2021)

  25. Di Scala, C., Yahi, N., Boutemeur, S., Flores, A., Rodriguez, L., Chahinian, H., Fantini, J.: Common molecular mechanism of amyloid pore formation by Alzheimer’s β-amyloid peptide and α-synuclein. Sci. Rep. 6, 28781 (2016)

    Article  PubMed  PubMed Central  Google Scholar 

  26. Di Scala, C., Yahi, N., Flores, A., Boutemeur, S., Kourdougli, N., Chahinian, H., Fantini, J.: Broad neutralization of calcium-permeable amyloid pore channels with a chimeric Alzheimer/Parkinson peptide targeting brain gangliosides. Biochim. Biophys. Acta 1862, 213–222 (2016)

    Article  PubMed  Google Scholar 

  27. Fantini, J., Yahi, N.: Molecular insights into amyloid regulation by membrane cholesterol and sphingolipids: common mechanisms in neurodegenerative diseases. Expert Rev. Mol. Med. 12, e27 (2010)

  28. Fanning, S., Selkoe, D., Dettmer, U.: Parkinson’s disease: proteinopathy or lipidopathy? NPJ Parkinsons Dis. 6, 3 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Mori, A., Imai, Y., Hattori, N.: Lipids: Key Players That Modulate α-Synuclein Toxicity and Neurodegeneration in Parkinson's Disease. Int. J. Mol. Sci. 21, (2020)

  30. Follett, J., Darlow, B., Wong, M.B., Goodwin, J., Pountney, D.L.: Potassium depolarization and raised calcium induces α-synuclein aggregates. Neurotox. Res. 23, 378–392 (2013)

    Article  CAS  PubMed  Google Scholar 

  31. Shrivastava, A.N., Aperia, A., Melki, R., Triller, A.: Physico-Pathologic Mechanisms Involved in Neurodegeneration: Misfolded Protein-Plasma Membrane Interactions. Neuron 95, 33–50 (2017)

    Article  CAS  PubMed  Google Scholar 

  32. Kiechle, M., Grozdanov, V., Danzer, K.M.: The role of lipids in the initiation of α-synuclein misfolding. Front. Cell. Dev. Biol. 8, 562241 (2020)

  33. Mesa-Herrera, F., Taoro-González, L., Valdés-Baizabal, C., Diaz, M., Marín, R.: Lipid and lipid raft alteration in aging and neurodegenerative diseases: a window for the development of new biomarkers. Int. J. Mol. Sci. 20, (2019)

  34. Schmidt, F., Levin, J., Kamp, F., Kretzschmar, H., Giese, A., Bötzel, K.: Single-channel electrophysiology reveals a distinct and uniform pore complex formed by α-synuclein oligomers in lipid membranes. PLoS One 7, e42545 (2012)

  35. Quist, A., Doudevski, I., Lin, H., Azimova, R., Ng, D., Frangione, B., Kagan, B., Ghiso, J., Lal, R.: Amyloid ion channels: a common structural link for protein-misfolding disease. Proc. Natl. Acad. Sci. U. S. A. 102, 10427–10432 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Bengoa-Vergniory, N., Roberts, R.F., Wade-Martins, R., Alegre-Abarrategui, J.: Alpha-synuclein oligomers: a new hope. Acta Neuropathol. 134, 819–838 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Venko, K., Novič, M., Stoka, V., Žerovnik, E.: Prediction of transmembrane regions, cholesterol and ganglioside binding sites in amyloid-forming proteins indicate potential for amyloid pore formation. Front. Mol. Neurosci. 14, 619496 (2021)

  38. Malchiodi-Albedi, F., Paradisi, S., Matteucci, A., Frank, C., Diociaiuti, M.: Amyloid oligomer neurotoxicity, calcium dysregulation, and lipid rafts. Int. J. Alzheimers Dis. 2011, 906964. (2011)

  39. Martinez, Z., Zhu, M., Han, S., Fink, A.L.: GM1 specifically interacts with alpha-synuclein and inhibits fibrillation. Biochemistry 46, 1868–1877 (2007)

    Article  CAS  PubMed  Google Scholar 

  40. Gallegos, S., Pacheco, C., Peters, C., Opazo, C.M., Aguayo, L.G.: Features of alpha-synuclein that could explain the progression and irreversibility of Parkinson’s disease. Front. Neurosci. 9, 59 (2015)

    Article  PubMed  PubMed Central  Google Scholar 

  41. 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. 1863, 183536 (2021)

  42. Ingelsson, M.: Alpha-Synuclein Oligomers-Neurotoxic Molecules in Parkinson’s Disease and Other Lewy Body Disorders. Front. Neurosci. 10, 408 (2016)

    Article  PubMed  PubMed Central  Google Scholar 

  43. Luth, E.S., Stavrovskaya, I.G., Bartels, T., Kristal, B.S., Selkoe, D.J.: Soluble, prefibrillar α-synuclein oligomers promote complex I-dependent, Ca2+-induced mitochondrial dysfunction. J. Biol. Chem. 289, 21490–21507 (2014)

    Article  PubMed  PubMed Central  Google Scholar 

  44. Abramov, A.Y., Potapova, E.V., Dremin, V.V., Dunaev, A.V.: Interaction of oxidative stress and misfolded proteins in the mechanism of neurodegeneration. Life (Basel) 10, (2020)

  45. Pan, L., Meng, L., He, M., Zhang, Z.: Tau in the pathophysiology of Parkinson's disease. J. Mol. Neurosci. (2021)

  46. Kawakami, F., Suzuki, M., Shimada, N., Kagiya, G., Ohta, E., Tamura, K., Maruyama, H., Ichikawa, T.: Stimulatory effect of α-synuclein on the tau-phosphorylation by GSK-3β. FEBS J. 278, 4895–4904 (2011)

    Article  CAS  PubMed  Google Scholar 

  47. Danzer, K.M., Kranich, L.R., Ruf, W.P., Cagsal-Getkin, O., Winslow, A.R., Zhu, L., Vanderburg, C.R., McLean, P.J.: Exosomal cell-to-cell transmission of alpha synuclein oligomers. Mol. Neurodegener. 7, 42 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Emmanouilidou, E., Melachroinou, K., Roumeliotis, T., Garbis, S.D., Ntzouni, M., Margaritis, L.H., Stefanis, L., Vekrellis, K.: Cell-produced alpha-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival. J. Neurosci. 30, 6838–6851 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Tarutani, A., Hasegawa, M.: Prion-like propagation of α-synuclein in neurodegenerative diseases. Prog. Mol. Biol. Transl. Sci. 168, 323–348 (2019)

    Article  CAS  PubMed  Google Scholar 

  50. Quek, C., Hill, A.F.: The role of extracellular vesicles in neurodegenerative diseases. Biochem. Biophys. Res. Commun. 483, 1178–1186 (2017)

    Article  CAS  PubMed  Google Scholar 

  51. Melachroinou, K., Xilouri, M., Emmanouilidou, E., Masgrau, R., Papazafiri, P., Stefanis, L., Vekrellis, K.: Deregulation of calcium homeostasis mediates secreted α-synuclein-induced neurotoxicity. Neurobiol. Aging 34, 2853–2865 (2013)

    Article  CAS  PubMed  Google Scholar 

  52. Guardia-Laguarta, C., Area-Gomez, E., Rüb, C., Liu, Y., Magrané, J., Becker, D., Voos, W., Schon, E.A., Przedborski, S.: α-Synuclein is localized to mitochondria-associated ER membranes. J. Neurosci. 34, 249–259 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Ghio, S., Camilleri, A., Caruana, M., Ruf, V.C., Schmidt, F., Leonov, A., Ryazanov, S., Griesinger, C., Cauchi, R.J., Kamp, F., et al.: Cardiolipin promotes pore-forming activity of alpha-synuclein oligomers in mitochondrial membranes. ACS Chem. Neurosci. 10, 3815–3829 (2019)

    Article  CAS  PubMed  Google Scholar 

  54. Rcom-H’cheo-Gauthier, A.N., Osborne, S.L., Meedeniya, A.C., Pountney, D.L.: Calcium: Alpha-Synuclein Interactions in Alpha-Synucleinopathies. Front. Neurosci. 10, 570 (2016)

    Article  PubMed  PubMed Central  Google Scholar 

  55. Zakharov, S.D., Hulleman, J.D., Dutseva, E.A., Antonenko, Y.N., Rochet, J.C., Cramer, W.A.: Helical alpha-synuclein forms highly conductive ion channels. Biochemistry 46, 14369–14379 (2007)

    Article  CAS  PubMed  Google Scholar 

  56. Angelova, P.R., Ludtmann, M.H., Horrocks, M.H., Negoda, A., Cremades, N., Klenerman, D., Dobson, C.M., Wood, N.W., Pavlov, E.V., Gandhi, S., Abramov, A.Y.: Ca2+ is a key factor in α-synuclein-induced neurotoxicity. J. Cell. Sci. 129, 1792–1801 (2016)

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Fantini, J., Yahi, N.: Brain lipids in synaptic function and neurological disease. Elsevier Academic Press, Clues to innovative therapeutic strategies for brain disorders. (2015)

    Google Scholar 

  58. Runwal, G., Edwards, R.H.: The Membrane Interactions of Synuclein: Physiology and Pathology. Annu. Rev. Pathol. 16, 465–485 (2021)

    Article  CAS  PubMed  Google Scholar 

  59. Schengrund, C.L.: Lipid rafts: keys to neurodegeneration. Brain Res. Bull. 82, 7–17 (2010)

    Article  CAS  PubMed  Google Scholar 

  60. Kraĉun, I., Rösner, H., Cosović, C., Stavljenić, A.: Topographical atlas of the gangliosides of the adult human brain. J. Neurochem. 43, 979–989 (1984)

    Article  PubMed  Google Scholar 

  61. Lindström, V., Gustafsson, G., Sanders, L.H., Howlett, E.H., Sigvardson, J., Kasrayan, A., Ingelsson, M., Bergström, J., Erlandsson, A.: Extensive uptake of α-synuclein oligomers in astrocytes results in sustained intracellular deposits and mitochondrial damage. Mol. Cell. Neurosci. 82, 143–156 (2017)

    Article  PubMed  Google Scholar 

  62. Phatnani, H., Maniatis, T.: Astrocytes in neurodegenerative disease. Cold Spring Harb.Perspect. Biol. 7, (2015)

  63. Asou, H., Hirano, S., Uyemura, K.: Ganglioside composition of astrocytes. Cell. Struct. Funct. 14, 561–568 (1989)

    Article  CAS  PubMed  Google Scholar 

  64. Liu, C., Zhao, Y., Xi, H., Jiang, J., Yu, Y., Dong, W.: The Membrane Interaction of Alpha-Synuclein. Front. Cell. Neurosci. 15, (2021)

  65. Seyfried, T.N., Choi, H., Chevalier, A., Hogan, D., Akgoc, Z., Schneider, J.S.: Sex-Related Abnormalities in Substantia Nigra Lipids in Parkinson’s Disease. ASN Neuro 10, 1759091418781889 (2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Huebecker, M., Moloney, E.B., van der Spoel, A.C., Priestman, D.A., Isacson, O., Hallett, P.J., Platt, F.M.: Reduced sphingolipid hydrolase activities, substrate accumulation and ganglioside decline in Parkinson’s disease. Mol. Neurodegener. 14, 40 (2019)

    Article  PubMed  PubMed Central  Google Scholar 

  67. Svennerholm, L., Boström, K., Jungbjer, B., Olsson, L.: Membrane lipids of adult human brain: lipid composition of frontal and temporal lobe in subjects of age 20 to 100 years. J. Neurochem. 63, 1802–1811 (1994)

    Article  CAS  PubMed  Google Scholar 

  68. Fantini, J., Yahi, N.: Molecular basis for the glycosphingolipid-binding specificity of α-synuclein: key role of tyrosine 39 in membrane insertion. J. Mol. Biol. 408, 654–669 (2011)

    Article  CAS  PubMed  Google Scholar 

  69. Gaspar, R., Pallbo, J., Weininger, U., Linse, S., Sparr, E.: Ganglioside lipids accelerate α-synuclein amyloid formation. Biochim. Biophys. Acta Proteins Proteom. 1866, 1062–1072 (2018)

    Article  CAS  Google Scholar 

  70. Perissinotto, F., Rondelli, V., Parisse, P., Tormena, N., Zunino, A., Almásy, L., Merkel, D.G., Bottyán, L., Sajti, S., Casalis, L.: GM1 Ganglioside role in the interaction of Alpha-synuclein with lipid membranes: Morphology and structure. Biophys. Chem. 255, 106272 (2019)

  71. Di Pasquale, E., Fantini, J., Chahinian, H., Maresca, M., Taïeb, N., Yahi, N.: Altered ion channel formation by the Parkinson’s-disease-linked E46K mutant of alpha-synuclein is corrected by GM3 but not by GM1 gangliosides. J. Mol. Biol. 397, 202–218 (2010)

    Article  PubMed  Google Scholar 

  72. Fantini, J., Yahi, N.: The driving force of alpha-synuclein insertion and amyloid channel formation in the plasma membrane of neural cells: key role of ganglioside- and cholesterol-binding domains. Adv. Exp. Med. Biol. 991, 15–26 (2013)

    Article  CAS  PubMed  Google Scholar 

  73. Yahi, N., Fantini, J.: Deciphering the glycolipid code of Alzheimer's and Parkinson's amyloid proteins allowed the creation of a universal ganglioside-binding peptide. PLoS One 9,e104751 (2014)

  74. Lautenschläger, J., Stephens, A.D., Fusco, G., Ströhl, F., Curry, N., Zacharopoulou, M., Michel, C.H., Laine, R., Nespovitaya, N., Fantham, M., et al.: C-terminal calcium binding of α-synuclein modulates synaptic vesicle interaction. Nat. Commun. 9, 712 (2018)

    Article  PubMed  PubMed Central  Google Scholar 

  75. Fantini, J., Carlus, D., Yahi, N.: The fusogenic tilted peptide (67–78) of α-synuclein is a cholesterol binding domain. Biochim. Biophys. Acta 1808, 2343–2351 (2011)

    Article  CAS  PubMed  Google Scholar 

  76. Jakubec, M., Bariås, E., Furse, S., Govasli, M.L., George, V., Turcu, D., Iashchishyn, I.A., Morozova-Roche, L.A., Halskau, Ø.: Cholesterol-containing lipid nanodiscs promote an α-synuclein binding mode that accelerates oligomerization. FEBS J. 288, 1887–1905 (2021)

    Article  CAS  PubMed  Google Scholar 

  77. Jakubec, M., Bariås, E., Furse, S., Govasli, M.L., George, V., Turcu, D., Iashchishyn, I., Morozova-Roche, L., Halskau, Ø.: Cholesterol is a strong promotor of an α-Synuclein membrane binding mode that accelerates oligomerization. bioRxiv 725762 (2019)

  78. Fantini, J., Chahinian, H., Yahi, N.: Progress toward Alzheimer’s disease treatment: Leveraging the Achilles’ heel of Aβ oligomers? Protein Sci. 29, 1748–1759 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Scollo, F., La Rosa, C.: Amyloidogenic intrinsically disordered proteins: new insights into their self-assembly and their interaction with membranes. Life (Basel) 10, (2020)

  80. Conway, K.A., Lee, S.J., Rochet, J.C., Ding, T.T., Williamson, R.E., Lansbury, P.T., Jr.: Acceleration of oligomerization, not fibrillization, is a shared property of both alpha-synuclein mutations linked to early-onset Parkinson’s disease: implications for pathogenesis and therapy. Proc. Natl. Acad Sci. U. S. A. 97, 571–576 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Robinson, J.L., Lee, E.B., Xie, S.X., Rennert, L., Suh, E., Bredenberg, C., Caswell, C., Van Deerlin, V.M., Yan, N., Yousef, A., et al.: Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated. Brain 141, 2181–2193 (2018)

    Article  PubMed  PubMed Central  Google Scholar 

  82. Hamilton, R.L.: Lewy bodies in Alzheimer’s disease: a neuropathological review of 145 cases using alpha-synuclein immunohistochemistry. Brain Pathol. 10, 378–384 (2000)

    Article  CAS  PubMed  Google Scholar 

  83. Spires-Jones, T.L., Attems, J., Thal, D.R.: Interactions of pathological proteins in neurodegenerative diseases. Acta Neuropathol. 134, 187–205 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Lippa, C.F., Fujiwara, H., Mann, D.M., Giasson, B., Baba, M., Schmidt, M.L., Nee, L.E., O’Connell, B., Pollen, D.A., St George-Hyslop, P., et al.: Lewy bodies contain altered alpha-synuclein in brains of many familial Alzheimer’s disease patients with mutations in presenilin and amyloid precursor protein genes. Am. J. Pathol. 153, 1365–1370 (1998)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Compta, Y., Revesz, T.: Neuropathological and biomarker findings in Parkinson’s disease and Alzheimer’s disease: from protein aggregates to synaptic dysfunction. J. Parkinsons Dis. 11, 107–121 (2021)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Kayed, R., Dettmer, U., Lesné, S.E.: Soluble endogenous oligomeric α-synuclein species in neurodegenerative diseases: Expression, spreading, and cross-talk. J. Parkinsons Dis. 10, 791–818 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Schneider, J.S., Gollomp, S.M., 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. 324, 140–148 (2013)

    Article  CAS  PubMed  Google Scholar 

  88. Ledeen, R.W., Wu, G.: The multi-tasked life of GM1 ganglioside, a true factotum of nature. Trends Biochem. Sci. 40, 407–418 (2015)

    Article  CAS  PubMed  Google Scholar 

  89. Fallon, L., Moreau, F., Croft, B.G., Labib, N., Gu, W.J., Fon, E.A.: Parkin and CASK/LIN-2 associate via a PDZ-mediated interaction and are co-localized in lipid rafts and postsynaptic densities in brain. J. Biol. Chem. 277, 486–491 (2002)

    Article  CAS  PubMed  Google Scholar 

  90. Hatano, T., Kubo, S., Imai, S., Maeda, M., Ishikawa, K., Mizuno, Y., Hattori, N.: Leucine-rich repeat kinase 2 associates with lipid rafts. Hum. Mol. Genet. 16, 678–690 (2007)

    Article  CAS  PubMed  Google Scholar 

  91. Schneider, J.S., Kean, A., DiStefano, L.: GM1 ganglioside rescues substantia nigra pars compacta neurons and increases dopamine synthesis in residual nigrostriatal dopaminergic neurons in MPTP-treated mice. J. Neurosci. Res. 42, 117–123 (1995)

    Article  CAS  PubMed  Google Scholar 

  92. Wu, G., Lu, Z.H., Kulkarni, N., Ledeen, R.W.: Deficiency of ganglioside GM1 correlates with Parkinson’s disease in mice and humans. J. Neurosci. Res. 90, 1997–2008 (2012)

    Article  CAS  PubMed  Google Scholar 

  93. Sipione, S., Monyror, J., Galleguillos, D., Steinberg, N., Kadam, V.: Gangliosides in the Brain: Physiology, Pathophysiology and Therapeutic Applications. Front. Neurosci. 14, 572965 (2020)

  94. Chiricozzi, E., Mauri, L., Lunghi, G., Di Biase, E., Fazzari, M., Maggioni, M., Valsecchi, M., Prioni, S., Loberto, N., Pomè, D.Y., et al.: Parkinson’s disease recovery by GM1 oligosaccharide treatment in the B4galnt1(+/-) mouse model. Sci. Rep. 9, 19330 (2019)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Fazzari, M., Audano, M., Lunghi, G., Di Biase, E., Loberto, N., Mauri, L., Mitro, N., Sonnino, S., Chiricozzi, E.: The oligosaccharide portion of ganglioside GM1 regulates mitochondrial function in neuroblastoma cells. Glycoconj. J. 37, 293–306 (2020)

    Article  CAS  PubMed  Google Scholar 

  96. Di Biase, E., Lunghi, G., Maggioni, M., Fazzari, M., Pomè, D.Y., Loberto, N., Ciampa, M.G., Fato, P., Mauri, L., Sevin, E., et al.: GM1 oligosaccharide crosses the human blood-brain barrier in vitro by a Paracellular Route. Int. J. Mol. Sci. 21, (2020)

  97. Price, D.L., Koike, M.A., Khan, A., Wrasidlo, W., Rockenstein, E., Masliah, E., Bonhaus, D.: The small molecule alpha-synuclein misfolding inhibitor, NPT200-11, produces multiple benefits in an animal model of Parkinson’s disease. Sci. Rep. 8, 16165 (2018)

    Article  PubMed  PubMed Central  Google Scholar 

  98. Heras-Garvin, A., Weckbecker, D., Ryazanov, S., Leonov, A., Griesinger, C., Giese, A., Wenning, G.K., Stefanova, N.: Anle138b modulates α-synuclein oligomerization and prevents motor decline and neurodegeneration in a mouse model of multiple system atrophy. Mov. Disord. 34, 255–263 (2019)

    Article  CAS  PubMed  Google Scholar 

  99. Limbocker, R., Mannini, B., Ruggeri, F.S., Cascella, R., Xu, C.K., Perni, M., Chia, S., Chen, S.W., Habchi, J., Bigi, A., et al.: Trodusquemine displaces protein misfolded oligomers from cell membranes and abrogates their cytotoxicity through a generic mechanism. Commun. Biol. 3, 435 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Kreiser, R.P., Wright, A.K., Block, N.R., Hollows, J.E., Nguyen, L.T., LeForte, K., Mannini, B., Vendruscolo, M., Limbocker, R.: Therapeutic strategies to reduce the toxicity of misfolded protein oligomers. Int. J. Mol. Sci. 21, (2020)

  101. Wrasidlo, W., Tsigelny, I.F., Price, D.L., Dutta, G., Rockenstein, E., Schwarz, T.C., Ledolter, K., Bonhaus, D., Paulino, A., Eleuteri, S., et al.: A de novo compound targeting α-synuclein improves deficits in models of Parkinson’s disease. Brain 139, 3217–3236 (2016)

    Article  PubMed  PubMed Central  Google Scholar 

  102. Cummings, J.: Lessons Learned from Alzheimer Disease: Clinical Trials with Negative Outcomes. Clin. Transl. Sci. 11, 147–152 (2018)

    Article  PubMed  Google Scholar 

  103. Reardon, S.: Frustrated Alzheimer’s researchers seek better lab mice. Nature 563, 611–612 (2018)

    Article  CAS  PubMed  Google Scholar 

  104. Merchant, K.M., Cedarbaum, J.M., Brundin, P., Dave, K.D., Eberling, J., Espay, A.J., Hutten, S.J., Javidnia, M., Luthman, J., Maetzler, W., et al.: A Proposed Roadmap for Parkinson’s Disease Proof of Concept Clinical Trials Investigating Compounds Targeting Alpha-Synuclein. J. Parkinsons Dis. 9, 31–61 (2019)

    Article  PubMed  PubMed Central  Google Scholar 

  105. Melrose, H.L., Lincoln, S.J., Tyndall, G.M., Farrer, M.J.: Parkinson’s disease: a rethink of rodent models. Exp. Brain Res. 173, 196–204 (2006)

    Article  PubMed  Google Scholar 

  106. Geerts, H.: Of mice and men: bridging the translational disconnect in CNS drug discovery. CNS Drugs 23, 915–926 (2009)

    Article  CAS  PubMed  Google Scholar 

  107. Magen, I., Chesselet, M.F.: Genetic mouse models of Parkinson’s disease The state of the art. Prog. Brain Res. 184, 53–87 (2010)

    Article  CAS  PubMed  Google Scholar 

  108. Bezard, E., Yue, Z., Kirik, D., Spillantini, M.G.: Animal models of Parkinson’s disease: limits and relevance to neuroprotection studies. Mov. Disord. 28, 61–70 (2013)

    Article  CAS  PubMed  Google Scholar 

  109. Kin, K., Yasuhara, T., Kameda, M., Date, I.: Animal models for Parkinson's disease research: trends in the 2000s. Int. J. Mol. Sci. 20, (2019)

  110. Zeiss, C.J., Allore, H.G., Beck, A.P.: Established patterns of animal study design undermine translation of disease-modifying therapies for Parkinson's disease. PLoS One 12, e0171790 (2017)

  111. Potashkin, J.A., Blume, S.R., Runkle, N.K.: Limitations of animal models of Parkinson's disease. Parkinsons Dis. 2011, 658083 (2010)

  112. Hadaczek, P., Wu, G., Sharma, N., Ciesielska, A., Bankiewicz, K., Davidow, A.L., Lu, Z.H., Forsayeth, J., Ledeen, R.W.: GDNF signaling implemented by GM1 ganglioside; failure in Parkinson’s disease and GM1-deficient murine model. Exp. Neurol. 263, 177–189 (2015)

    Article  CAS  PubMed  Google Scholar 

  113. Wu, G., Lu, Z.H., Seo, J.H., Alselehdar, S.K., DeFrees, S., Ledeen, R.W.: Mice deficient in GM1 manifest both motor and non-motor symptoms of Parkinson's disease; successful treatment with synthetic GM1 ganglioside. Exp. Neurol. 329, 113284 (2020)

  114. Schneider, J.S., Seyfried, T.N., Choi, H.S., Kidd, S.K.: Intraventricular sialidase administration enhances GM1 ganglioside expression and is partially neuroprotective in a mouse model of Parkinson's disease. PLoS One 10,e0143351 (2015)

  115. Brekk, O.R., Korecka, J.A., Crapart, C.C., Huebecker, M., MacBain, Z.K., Rosenthal, S.A., Sena-Esteves, M., Priestman, D.A., Platt, F.M., Isacson, O., Hallett, P.J.: Upregulating β-hexosaminidase activity in rodents prevents α-synuclein lipid associations and protects dopaminergic neurons from α-synuclein-mediated neurotoxicity. Acta Neuropathol. Commun. 8, 127 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Planche, V., Munsch, F., Pereira, B., de Schlichting, E., Vidal, T., Coste, J., Morand, D., de Chazeron, I., Derost, P., Debilly, B., et al.: Anatomical predictors of cognitive decline after subthalamic stimulation in Parkinson’s disease. Brain Struct. Funct. 223, 3063–3072 (2018)

    Article  PubMed  Google Scholar 

  117. Zarzycki, M.Z., Domitrz, I.: Stimulation-induced side effects after deep brain stimulation - a systematic review. Acta Neuropsychiatr. 32, 57–64 (2020)

    Article  PubMed  Google Scholar 

  118. Valldeoriola, F., Puig-Junoy, J., Puig-Peiró, R.: Cost analysis of the treatments for patients with advanced Parkinson’s disease: SCOPE study. J. Med. Econ. 16, 191–201 (2013)

    Article  PubMed  Google Scholar 

  119. Sperling, R.A., Jack, C.R., Jr., Black, S.E., Frosch, M.P., Greenberg, S.M., Hyman, B.T., Scheltens, P., Carrillo, M.C., Thies, W., Bednar, M.M., et al.: Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimers Dement. 7, 367–385 (2011)

    Article  PubMed  PubMed Central  Google Scholar 

  120. Bittar, A., Sengupta, U., Kayed, R.: Prospects for strain-specific immunotherapy in Alzheimer’s disease and tauopathies. NPJ Vaccines 3, 9 (2018)

    Article  PubMed  PubMed Central  Google Scholar 

  121. Gonzalez-Garcia, M., Fusco, G., De Simone, A.: Membrane interactions and toxicity by misfolded protein oligomers. Front. Cell. Dev. Biol. 9, 642623 (2021)

  122. Magistretti, P.J., Geisler, F.H., Schneider, J.S., Li, P.A., Fiumelli, H., Sipione, S.: Gangliosides: Treatment Avenues in Neurodegenerative Disease. Front. Neurol. 10, 859 (2019)

    Article  PubMed  PubMed Central  Google Scholar 

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Correspondence to Jacques Fantini.

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N. Y. and J. F. are co-inventors of the AmyP53 peptide (patent Application EP15709163.8A), currently under development by AmyPore (France). H. C. is President of the Ethics and Scientific Committee of AmyPore. C. D. is member of the Ethics and Scientific Committee of AmyPore.

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Yahi, N., Di Scala, C., Chahinian, H. et al. Innovative treatment targeting gangliosides aimed at blocking the formation of neurotoxic α-synuclein oligomers in Parkinson’s disease. Glycoconj J 39, 1–11 (2022). https://doi.org/10.1007/s10719-021-10012-0

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