Immunotherapy in Parkinson's Disease: Micromanaging Alpha-Synuclein Aggregation

Overview

Journal J Parkinsons Dis

Publisher Sage Publications

Specialty Neurology

Date 2015 Sep 26

PMID 26406122

Citations 44

Authors

Sonia George

Patrik Brundin

Affiliations

Soon will be listed here.

Abstract

Currently, several α-synuclein immunotherapies are being tested in experimental Parkinson's disease models and in clinical trials. Recent research has revealed that α-synuclein is not just an intracellular synaptic protein but also exists extracellularly. Moreover, the transfer of misfolded α-synuclein between cells might be a crucial step in the process leading to a progressive increase in deposition of α-synuclein aggregates throughout the Parkinson's disease brain. The revelation that α-synuclein is present outside cells has increased the interest in antibody-based therapies and opens up for the notion that microglia might play a key role in retarding Parkinson's disease progression. The objectives of this review are to describe and contrast the use of active and passive immunotherapy in treating α-synucleinopathies and highlight the likely important role of microglia in clearing misfolded α-synuclein from the extracellular space.

Citing Articles

Sentinels of neuroinflammation: the crucial role of myeloid cells in the pathogenesis of gliomas and neurodegenerative diseases.

Comitre-Mariano B, Vellila-Alonso G, Segura-Collar B, Mondejar-Ruescas L, Sepulveda J, Gargini R J Neuroinflammation. 2024; 21(1):304.

PMID: 39578808 PMC: 11583668. DOI: 10.1186/s12974-024-03298-y.

Advances in clinical basic research: Performance, treatments, and mechanisms of Parkinson disease.

Yang T, Liu Y, Li J, Xu H, Li S, Xiong L Ibrain. 2023; 7(4):362-378.

PMID: 37786563 PMC: 10529016. DOI: 10.1002/ibra.12011.

Drug Discovery and Development Targeting Dementia.

Zagorska A, Czopek A, Fryc M, Jaromin A, Boyd B Pharmaceuticals (Basel). 2023; 16(2).

PMID: 37259302 PMC: 9965722. DOI: 10.3390/ph16020151.

The Management of Parkinson's Disease: An Overview of the Current Advancements in Drug Delivery Systems.

Nakmode D, Day C, Song Y, Garg S Pharmaceutics. 2023; 15(5).

PMID: 37242745 PMC: 10223383. DOI: 10.3390/pharmaceutics15051503.

Anti-inflammatory, anti-apoptotic, and neuroprotective potentials of anethole in Parkinson's disease-like motor and non-motor symptoms induced by rotenone in rats.

Vastegani S, Khoshnam S, Mansouri E, Ghafouri S, Bakhtiari N, Farbood Y Metab Brain Dis. 2023; 38(6):2159-2174.

PMID: 37204660 DOI: 10.1007/s11011-023-01230-6.

References

Nasstrom T, Goncalves S, Sahlin C, Nordstrom E, Sundquist V, Lannfelt L . Antibodies against alpha-synuclein reduce oligomerization in living cells. PLoS One. 2011; 6(10):e27230. PMC: 3205056. DOI: 10.1371/journal.pone.0027230. View

Mandler M, Valera E, Rockenstein E, Weninger H, Patrick C, Adame A . Next-generation active immunization approach for synucleinopathies: implications for Parkinson's disease clinical trials. Acta Neuropathol. 2014; 127(6):861-79. PMC: 4034750. DOI: 10.1007/s00401-014-1256-4. View

El-Agnaf O, Salem S, Paleologou K, Cooper L, Fullwood N, Gibson M . Alpha-synuclein implicated in Parkinson's disease is present in extracellular biological fluids, including human plasma. FASEB J. 2003; 17(13):1945-7. DOI: 10.1096/fj.03-0098fje. View

Masliah E, Rockenstein E, Adame A, Alford M, Crews L, Hashimoto M . Effects of alpha-synuclein immunization in a mouse model of Parkinson's disease. Neuron. 2005; 46(6):857-68. DOI: 10.1016/j.neuron.2005.05.010. View

Lee G, Dallas S, Hong M, Bendayan R . Drug transporters in the central nervous system: brain barriers and brain parenchyma considerations. Pharmacol Rev. 2001; 53(4):569-96. View

Lindstrom V, Fagerqvist T, Nordstrom E, Eriksson F, Lord A, Tucker S . Immunotherapy targeting α-synuclein protofibrils reduced pathology in (Thy-1)-h[A30P] α-synuclein mice. Neurobiol Dis. 2014; 69:134-43. DOI: 10.1016/j.nbd.2014.05.009. View

Duffy K, Pardridge W . Blood-brain barrier transcytosis of insulin in developing rabbits. Brain Res. 1987; 420(1):32-8. DOI: 10.1016/0006-8993(87)90236-8. View

Aguzzi A, Rajendran L . The transcellular spread of cytosolic amyloids, prions, and prionoids. Neuron. 2010; 64(6):783-90. DOI: 10.1016/j.neuron.2009.12.016. View

Proukakis C, Dudzik C, Brier T, Mackay D, Cooper J, Millhauser G . A novel α-synuclein missense mutation in Parkinson disease. Neurology. 2013; 80(11):1062-4. PMC: 3653201. DOI: 10.1212/WNL.0b013e31828727ba. View

10.

Marques O, Outeiro T . Alpha-synuclein: from secretion to dysfunction and death. Cell Death Dis. 2012; 3:e350. PMC: 3406593. DOI: 10.1038/cddis.2012.94. View

11.

Li J, Englund E, Holton J, Soulet D, Hagell P, Lees A . Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nat Med. 2008; 14(5):501-3. DOI: 10.1038/nm1746. View

12.

Roberts R, Wade-Martins R, Alegre-Abarrategui J . Direct visualization of alpha-synuclein oligomers reveals previously undetected pathology in Parkinson's disease brain. Brain. 2015; 138(Pt 6):1642-57. PMC: 4614141. DOI: 10.1093/brain/awv040. View

13.

Masliah E, Rockenstein E, Mante M, Crews L, Spencer B, Adame A . Passive immunization reduces behavioral and neuropathological deficits in an alpha-synuclein transgenic model of Lewy body disease. PLoS One. 2011; 6(4):e19338. PMC: 3084838. DOI: 10.1371/journal.pone.0019338. View

14.

Fagerqvist T, Lindstrom V, Nordstrom E, Lord A, Tucker S, Su X . Monoclonal antibodies selective for α-synuclein oligomers/protofibrils recognize brain pathology in Lewy body disorders and α-synuclein transgenic mice with the disease-causing A30P mutation. J Neurochem. 2013; 126(1):131-44. DOI: 10.1111/jnc.12175. View

15.

Valera E, Masliah E . Immunotherapy for neurodegenerative diseases: focus on α-synucleinopathies. Pharmacol Ther. 2013; 138(3):311-22. PMC: 3925783. DOI: 10.1016/j.pharmthera.2013.01.013. View

16.

Mandler M, Valera E, Rockenstein E, Mante M, Weninger H, Patrick C . Active immunization against alpha-synuclein ameliorates the degenerative pathology and prevents demyelination in a model of multiple system atrophy. Mol Neurodegener. 2015; 10:10. PMC: 4411775. DOI: 10.1186/s13024-015-0008-9. View

17.

Rockenstein E, Mallory M, Hashimoto M, Song D, Shults C, Lang I . Differential neuropathological alterations in transgenic mice expressing alpha-synuclein from the platelet-derived growth factor and Thy-1 promoters. J Neurosci Res. 2002; 68(5):568-78. DOI: 10.1002/jnr.10231. View

18.

Kruger R, Kuhn W, Muller T, Woitalla D, Graeber M, Kosel S . Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. Nat Genet. 1998; 18(2):106-8. DOI: 10.1038/ng0298-106. View

19.

Nalls M, Pankratz N, Lill C, Do C, Hernandez D, Saad M . Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nat Genet. 2014; 46(9):989-93. PMC: 4146673. DOI: 10.1038/ng.3043. View

20.

Chu Y, Kordower J . The prion hypothesis of Parkinson's disease. Curr Neurol Neurosci Rep. 2015; 15(5):28. DOI: 10.1007/s11910-015-0549-x. View