Objective: To identify seeding capacities of soluble α-synuclein (α-syn) conformers derived from neuronal extracellular vesicles (NEs) from Parkinson´s disease (PD) patients.
Background: PD pathology is characterized by the aggregation of the synaptic protein α-syn that is able to form toxic oligomers as well as insoluble amyloid fibrils and causes cell death of neurons. These pathological conformers can be transmitted from cell to cell and are able to induce physiological, monomeric α-syn to form also pathological structures (prion-like propagation of protein misfolding and aggregation).
Method: We studied 30 PD patients and 50 controls from our in- and outpatient clinic. After clinical examination and blood collection, extracellular vesicles were isolated from blood plasma. Next, neuron-derived extracellular vesicles (NEs) were purified from the total of vesicles. In subsequent analyses we performed α-syn amplification assays using PD- and control-NEs to study potential seeding capacities of soluble NE-derived α-syn from PD patients and controls. Seeding assay end products were validated by immunoblots and transmission electron microscopy.
Results: For all 30 PD patients seeding of pathological protein folding could be demonstrated, whereas no seeding capacities were detected in the control cohort. Amplified α-syn conformers were visualized by transmission electron microscopy and showed fibrillary appearance. Using structure-specific antibodies, raised against amyloid epitopes of protein aggregates, significantly increased signal intensities were detected in seeding assay end products of PD-NEs.
Conclusion: We show that the amplification of pathological neuronal α-syn conformers is possible and demonstrate that the ability to trigger α-syn seeding has the potential for a reliable blood biomarker of PD pathology. Further studies should validate these findings.
To cite this abstract in AMA style:A. Kluge, J. Bunk, E. Schäffer, H. Knacke, A. Drobny, W. Xiang, R. Lucius, P. Arnold, F. Zunke, D. Berg. Blood-derived α-synuclein from Parkinson´s disease patients is able to seed pathology [abstract]. Mov Disord. 2022; 37 (suppl 2). https://www.mdsabstracts.org/abstract/blood-derived-%ce%b1-synuclein-from-parkinsons-disease-patients-is-able-to-seed-pathology/. Accessed September 28, 2023.
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MDS Abstracts - https://www.mdsabstracts.org/abstract/blood-derived-%ce%b1-synuclein-from-parkinsons-disease-patients-is-able-to-seed-pathology/