Objective: To investigate the protective efficacy of different alpha-synuclein (α-Syn)-targeting antibodies in a new model of α-Syn cell-to-cell spread.

Background: The 14 kDa protein α-Syn is considered to be a key player in the pathogenesis of Parkinson’s disease (PD) and dementia with Lewy bodies. Cell-to-cell transmission of α-Syn is the likely mechanism responsible for spreading pathology throughout the brain. However, the precise nature of the transmissible α-Syn species is still unknown. A primary goal in PD research is to find novel therapies to prevent disease progression. Passive immunotherapy using monoclonal antibodies is one possibility to achieve this goal. Tailoring antibodies to target defined transmissible α-Syn species could optimize  therapeutic efficacy and minimize potential side effects.

Method: In the present study, an in vitro model in Lund human mesencephalic (LUHMES) cells was established to quantify the protective efficacy of monoclonal antibodies targeting α-Syn. Death of GFP-expressing cells was monitored with optical read-outs, when co-cultured with α-Syn-overexpressing cells. Western blots were used to identify α-Syn species present in the cell culture medium. A spectrum of α-Syn-targeting antibodies was tested for differences in their epitope binding, their affinity towards α-Syn monomers, oligomers and aggregates (dot blot and Western blots), and their protective efficacy against α-Syn-induced toxicity.

Results: We found increasing degeneration of the GFP-expressing cell population with an increasing proportion of α-Syn-overexpressing cells in the co-culture. In this model, a subset of monoclonal α-Syn-specific antibodies against C-terminal or N-terminal part of α-Syn protected the GFP-expressing cells from cell death to a variable extent. The affinity towards monomeric recombinant α-Syn was not sufficient to explain the relative protective efficacy of the antibodies. The tested antibodies, however, showed different affinity towards distinct α-Syn species in the medium (fragments, monomers,  oligomers, fibrils), which correlated with the protective efficacy.

Conclusion: Our new model generates relevant insights into the nature of the α-Syn species involved in cell-to-cell spread and allows testing of α-Syn-specific antibodies as therapeutic agents for synucleinopathies.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/investigation-of-the-protective-efficacy-of-alpha-synuclein-specific-antibodies-in-a-novel-neuronal-cell-model-for-synucleinopathies/