Objective: To evaluate possible differences in the biological properties of alpha-synuclein fibrils derived from different patients with Parkinson’s disease.

Background: Parkinson’s disease (PD) is a clinically heterogeneous neurodegenerative disease characterized by Lewy bodies and neurites containing misfolded, aggregated alpha-synuclein (aSyn). Prion-like properties of aSyn aggregates contribute to the spread of neuropathology throughout the nervous system. aSyn seeds can be amplified from patient material such as cerebrospinal fluid, and our group has previously observed heterogeneity in the seeding behavior of aSyn seeds.

Method: In order to explore this heterogeneity further, we amplified aSyn seeds from cerebrospinal fluid samples of 20 patients with PD. The resulting fibrils were purified, adjusted in concentration, and transfected into aSyn-overexpressing HEK293T cells. The seeding of intracellular aSyn pathology was quantified using automated high-throughput microscopy and image analysis after staining for phosphorylated aSyn.

Results: Fibrils derived from distinct patients differ in their capacity to seed cellular aSyn pathology, and these seeding properties correlate with clinical parameters.

Conclusion: Our findings are consistent with the hypothesis that aSyn can form structurally distinct types of aggregates. They suggest that distinct strains may exist in patients with PD. This property could facilitate the stratification of patients with PD into prognostic subgroups and for disease-modifying clinical trials.

References: Previously presented at CURE-ND workshop, March 19th, 2024

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MDS Abstracts - https://www.mdsabstracts.org/abstract/discriminating-alpha-synuclein-strains-in-parkinsons-disease/