An Antibody Scanning Method for the Detection of α-synuclein Oligomers in the Serum of Parkinson's Disease Patients

Overview

Journal Chem Sci

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2022 Dec 22

PMID 36544716

Authors

Klara Kulenkampff

Derya Emin

Roxine Staats

Yu P Zhang

Laila Sakhnini

Antonina Kouli

Oded Rimon

Evgeniia Lobanova

Caroline H Williams-Gray

Francesco A Aprile

Pietro Sormanni

David Klenerman

Michele Vendruscolo

Affiliations

Soon will be listed here.

Abstract

Misfolded α-synuclein oligomers are closely implicated in the pathology of Parkinson's disease and related synucleinopathies. The elusive nature of these aberrant assemblies makes it challenging to develop quantitative methods to detect them and modify their behavior. Existing detection methods use antibodies to bind α-synuclein aggregates in biofluids, although it remains challenging to raise antibodies against α-synuclein oligomers. To address this problem, we used an antibody scanning approach in which we designed a panel of 9 single-domain epitope-specific antibodies against α-synuclein. We screened these antibodies for their ability to inhibit the aggregation process of α-synuclein, finding that they affected the generation of α-synuclein oligomers to different extents. We then used these antibodies to investigate the size distribution and morphology of soluble α-synuclein aggregates in serum and cerebrospinal fluid samples from Parkinson's disease patients. Our results indicate that the approach that we present offers a promising route for the development of antibodies to characterize soluble α-synuclein aggregates in biofluids.

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References

Guerrero-Ferreira R, Taylor N, Mona D, Ringler P, Lauer M, Riek R . Cryo-EM structure of alpha-synuclein fibrils. Elife. 2018; 7. PMC: 6092118. DOI: 10.7554/eLife.36402. View

McFarthing K, Buff S, Rafaloff G, Dominey T, Wyse R, Stott S . Parkinson's Disease Drug Therapies in the Clinical Trial Pipeline: 2020. J Parkinsons Dis. 2020; 10(3):757-774. PMC: 7458531. DOI: 10.3233/JPD-202128. View

Wang M, Yi S, Han J, Park S, Jang J, Chun I . Oligomeric forms of amyloid-β protein in plasma as a potential blood-based biomarker for Alzheimer's disease. Alzheimers Res Ther. 2017; 9(1):98. PMC: 5732503. DOI: 10.1186/s13195-017-0324-0. View

Li B, Ge P, Murray K, Sheth P, Zhang M, Nair G . Cryo-EM of full-length α-synuclein reveals fibril polymorphs with a common structural kernel. Nat Commun. 2018; 9(1):3609. PMC: 6127345. DOI: 10.1038/s41467-018-05971-2. View

Zuo L, Yu S, Wang F, Hu Y, Piao Y, Du Y . Parkinson's Disease with Fatigue: Clinical Characteristics and Potential Mechanisms Relevant to α-Synuclein Oligomer. J Clin Neurol. 2016; 12(2):172-80. PMC: 4828563. DOI: 10.3988/jcn.2016.12.2.172. View

Park M, Cheon S, Bae H, Kim S, Kim J . Elevated levels of α-synuclein oligomer in the cerebrospinal fluid of drug-naïve patients with Parkinson's disease. J Clin Neurol. 2012; 7(4):215-22. PMC: 3259496. DOI: 10.3988/jcn.2011.7.4.215. View

Lobanova E, Whiten D, Ruggeri F, Taylor C, Kouli A, Xia Z . Imaging protein aggregates in the serum and cerebrospinal fluid in Parkinson's disease. Brain. 2021; 145(2):632-643. PMC: 9014748. DOI: 10.1093/brain/awab306. View

Kumar S, Jagannath S, Francois C, Vanderstichele H, Stoops E, Lashuel H . How specific are the conformation-specific α-synuclein antibodies? Characterization and validation of 16 α-synuclein conformation-specific antibodies using well-characterized preparations of α-synuclein monomers, fibrils and oligomers with distinct.... Neurobiol Dis. 2020; 146:105086. DOI: 10.1016/j.nbd.2020.105086. View

Ng A, Tan Y, Lu Z, Ng E, Ng S, Chia N . Plasma alpha-synuclein detected by single molecule array is increased in PD. Ann Clin Transl Neurol. 2019; 6(3):615-619. PMC: 6414476. DOI: 10.1002/acn3.729. View

10.

Devi L, Raghavendran V, Prabhu B, Avadhani N, Anandatheerthavarada H . Mitochondrial import and accumulation of alpha-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain. J Biol Chem. 2008; 283(14):9089-100. PMC: 2431021. DOI: 10.1074/jbc.M710012200. 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.

Kulenkampff K, Wolf Perez A, Sormanni P, Habchi J, Vendruscolo M . Quantifying misfolded protein oligomers as drug targets and biomarkers in Alzheimer and Parkinson diseases. Nat Rev Chem. 2023; 5(4):277-294. DOI: 10.1038/s41570-021-00254-9. View

13.

Staats R, Michaels T, Flagmeier P, Chia S, Horne R, Habchi J . Screening of small molecules using the inhibition of oligomer formation in α-synuclein aggregation as a selection parameter. Commun Chem. 2023; 3(1):191. PMC: 9814678. DOI: 10.1038/s42004-020-00412-y. View

14.

Fields C, Bengoa-Vergniory N, Wade-Martins R . Targeting Alpha-Synuclein as a Therapy for Parkinson's Disease. Front Mol Neurosci. 2019; 12:299. PMC: 6906193. DOI: 10.3389/fnmol.2019.00299. View

15.

Aprile F, Sormanni P, Podpolny M, Chhangur S, Needham L, Ruggeri F . Rational design of a conformation-specific antibody for the quantification of Aβ oligomers. Proc Natl Acad Sci U S A. 2020; 117(24):13509-13518. PMC: 7306997. DOI: 10.1073/pnas.1919464117. View

16.

Guerrero-Ferreira R, Taylor N, Arteni A, Kumari P, Mona D, Ringler P . Two new polymorphic structures of human full-length alpha-synuclein fibrils solved by cryo-electron microscopy. Elife. 2019; 8. PMC: 6957273. DOI: 10.7554/eLife.48907. View

17.

Hsu L, Sagara Y, Arroyo A, Rockenstein E, Sisk A, Mallory M . alpha-synuclein promotes mitochondrial deficit and oxidative stress. Am J Pathol. 2000; 157(2):401-10. PMC: 1850140. DOI: 10.1016/s0002-9440(10)64553-1. View

18.

Sanderson J, De S, Jiang H, Rovere M, Jin M, Zaccagnini L . Analysis of α-synuclein species enriched from cerebral cortex of humans with sporadic dementia with Lewy bodies. Brain Commun. 2020; 2(1):fcaa010. PMC: 7130446. DOI: 10.1093/braincomms/fcaa010. View

19.

Spillantini M, Schmidt M, Lee V, Trojanowski J, Jakes R, Goedert M . Alpha-synuclein in Lewy bodies. Nature. 1997; 388(6645):839-40. DOI: 10.1038/42166. View

20.

Bourdenx M, Bezard E, Dehay B . Lysosomes and α-synuclein form a dangerous duet leading to neuronal cell death. Front Neuroanat. 2014; 8:83. PMC: 4132369. DOI: 10.3389/fnana.2014.00083. View