Treating Parkinson's Disease with Antibodies: Previous Studies and Future Directions

Overview

Journal J Parkinsons Dis

Publisher Sage Publications

Specialty Neurology

Date 2020 Oct 26

PMID 33104039

Citations 22

Authors

Anne-Marie Castonguay

Claude Gravel

Martin Levesque

Affiliations

Soon will be listed here.

Abstract

Parkinson's disease is a neurodegenerative disorder mainly characterized by the degeneration of dopaminergic neurons in the substantia nigra. Degenerating neurons contain abnormal aggregates called Lewy bodies, that are predominantly composed of the misfolded and/or mutated alpha-synuclein protein. Post-translational modifications, cellular stress, inflammation and gene mutations are thought to trigger its pathological misfolding and aggregation. With alpha-synuclein pathology being strongly associated with dopaminergic neuronal toxicity, strategies aimed to reduce its burden are expected to be beneficial in slowing disease progression. Moreover, multiple sources of evidence suggest a cell-to-cell transmission of pathological alpha-synuclein in a prion-like manner. Therefore, antibodies targeting extra- or intracellular alpha-synuclein could be efficient in limiting the aggregation and transmission. Several active and passive immunization strategies have been explored to target alpha-synuclein. Here, we summarize immunotherapeutic approaches that were tested in pre-clinical or clinical studies in the last two decades in an attempt to treat Parkinson's disease.

Citing Articles

Skull bone marrow and skull meninges channels: redefining the landscape of central nervous system immune surveillance.

Liu L, Zhang X, Chai Y, Zhang J, Deng Q, Chen X Cell Death Dis. 2025; 16(1):53.

PMID: 39875352 PMC: 11775313. DOI: 10.1038/s41419-025-07336-2.

Antibody-mediated clearance of an ER-resident aggregate that causes glaucoma.

Ma M, Qerqez A, Hill K, Azouz L, Youngblood H, Hill S PNAS Nexus. 2024; 4(1):pgae556.

PMID: 39726989 PMC: 11670252. DOI: 10.1093/pnasnexus/pgae556.

HDAC6 inhibitor-loaded brain-targeted nanocarrier-mediated neuroprotection in methamphetamine-driven Parkinson's disease.

Pham K, Khanal S, Bohara G, Rimal N, Song S, Nguyen T Redox Biol. 2024; 79():103457.

PMID: 39700694 PMC: 11722933. DOI: 10.1016/j.redox.2024.103457.

Unraveling neuroprotection in Parkinson's disease: Nrf2-Keap1 pathway's vital role amidst pathogenic pathways.

Kaur T, Sidana P, Kaur N, Choubey V, Kaasik A Inflammopharmacology. 2024; 32(5):2801-2820.

PMID: 39136812 DOI: 10.1007/s10787-024-01549-1.

Knocking down GRAMD1C expression reduces 6-OHDA-induced apoptosis in PC12 cells.

He H, Zhang B, Wang X, Chen L Toxicol Res (Camb). 2024; 13(2):tfae051.

PMID: 38638451 PMC: 11023001. DOI: 10.1093/toxres/tfae051.

References

Braak H, de Vos R, Bohl J, Del Tredici K . Gastric alpha-synuclein immunoreactive inclusions in Meissner's and Auerbach's plexuses in cases staged for Parkinson's disease-related brain pathology. Neurosci Lett. 2005; 396(1):67-72. DOI: 10.1016/j.neulet.2005.11.012. View

Bartels T, Choi J, Selkoe D . α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature. 2011; 477(7362):107-10. PMC: 3166366. DOI: 10.1038/nature10324. View

Cuervo A, Stefanis L, Fredenburg R, Lansbury P, Sulzer D . Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science. 2004; 305(5688):1292-5. DOI: 10.1126/science.1101738. View

Lashuel H, Overk C, Oueslati A, Masliah E . The many faces of α-synuclein: from structure and toxicity to therapeutic target. Nat Rev Neurosci. 2012; 14(1):38-48. PMC: 4295774. DOI: 10.1038/nrn3406. View

Polymeropoulos M, Lavedan C, Leroy E, Ide S, Dehejia A, Dutra A . Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science. 1997; 276(5321):2045-7. DOI: 10.1126/science.276.5321.2045. View

Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg M . alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol. 2002; 4(2):160-4. DOI: 10.1038/ncb748. View

Conway K, Harper J, Lansbury Jr P . Fibrils formed in vitro from alpha-synuclein and two mutant forms linked to Parkinson's disease are typical amyloid. Biochemistry. 2000; 39(10):2552-63. DOI: 10.1021/bi991447r. View

Danzer K, Kranich L, Ruf W, Cagsal-Getkin O, Winslow A, Zhu L . Exosomal cell-to-cell transmission of alpha synuclein oligomers. Mol Neurodegener. 2012; 7:42. PMC: 3483256. DOI: 10.1186/1750-1326-7-42. View

Volc D, Poewe W, Kutzelnigg A, Luhrs P, Thun-Hohenstein C, Schneeberger A . Safety and immunogenicity of the α-synuclein active immunotherapeutic PD01A in patients with Parkinson's disease: a randomised, single-blinded, phase 1 trial. Lancet Neurol. 2020; 19(7):591-600. DOI: 10.1016/S1474-4422(20)30136-8. View

10.

Lee J, Takahama S, Zhang G, Tomarev S, Ye Y . Unconventional secretion of misfolded proteins promotes adaptation to proteasome dysfunction in mammalian cells. Nat Cell Biol. 2016; 18(7):765-76. PMC: 10701763. DOI: 10.1038/ncb3372. View

11.

Winner B, Jappelli R, Maji S, Desplats P, Boyer L, Aigner S . In vivo demonstration that alpha-synuclein oligomers are toxic. Proc Natl Acad Sci U S A. 2011; 108(10):4194-9. PMC: 3053976. DOI: 10.1073/pnas.1100976108. View

12.

Masliah E, Rockenstein E, Veinbergs I, Sagara Y, Mallory M, Hashimoto M . beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease. Proc Natl Acad Sci U S A. 2001; 98(21):12245-50. PMC: 59799. DOI: 10.1073/pnas.211412398. View

13.

Mahul-Mellier A, Burtscher J, Maharjan N, Weerens L, Croisier M, Kuttler F . The process of Lewy body formation, rather than simply α-synuclein fibrillization, is one of the major drivers of neurodegeneration. Proc Natl Acad Sci U S A. 2020; 117(9):4971-4982. PMC: 7060668. DOI: 10.1073/pnas.1913904117. View

14.

Wang Y, Yan T, Lu H, Yin W, Lin B, Fan W . Lessons from Anti-Amyloid-β Immunotherapies in Alzheimer Disease: Aiming at a Moving Target. Neurodegener Dis. 2017; 17(6):242-250. DOI: 10.1159/000478741. View

15.

Kim C, Ho D, Suk J, You S, Michael S, Kang J . Neuron-released oligomeric α-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia. Nat Commun. 2013; 4:1562. PMC: 4089961. DOI: 10.1038/ncomms2534. View

16.

Lee H, Cho E, Lee K, Kim J, Cho S, Lee S . Autophagic failure promotes the exocytosis and intercellular transfer of α-synuclein. Exp Mol Med. 2013; 45:e22. PMC: 3674407. DOI: 10.1038/emm.2013.45. View

17.

Marzo L, Gousset K, Zurzolo C . Multifaceted roles of tunneling nanotubes in intercellular communication. Front Physiol. 2012; 3:72. PMC: 3322526. DOI: 10.3389/fphys.2012.00072. View

18.

Vaswani P, Olsen A . Immunotherapy in progressive supranuclear palsy. Curr Opin Neurol. 2020; 33(4):527-533. PMC: 7722007. DOI: 10.1097/WCO.0000000000000836. View

19.

Ulusoy A, Rusconi R, Perez-Revuelta B, Musgrove R, Helwig M, Winzen-Reichert B . Caudo-rostral brain spreading of α-synuclein through vagal connections. EMBO Mol Med. 2013; 5(7):1119-27. PMC: 3721477. DOI: 10.1002/emmm.201302475. View

20.

Parkkinen L, Pirttila T, Tervahauta M, Alafuzoff I . Widespread and abundant alpha-synuclein pathology in a neurologically unimpaired subject. Neuropathology. 2005; 25(4):304-14. DOI: 10.1111/j.1440-1789.2005.00644.x. View