Objective: To establish and characterize a robust alpha-synuclein (aSyn) aggregation pathology research model to allow efficient drug development platform for Parkinson’s disease (PD).

Background: PD is characterized by degeneration of dopamine neurons in the substantia nigra. Pathologically, occurrence of proteinaceous aggregates called Lewy bodies (LBs) is considered a hallmark of the disease, of which aSyn has been reported to be the primary component. The existing research models of PD have not been able to replicate these two characteristics reproducibly and robustly enough, resulting in inefficient models for drug discovery and testing. In addition to aSyn aggregation, dopamine neuron death in PD has been linked to many risk factors, one of them being oxidative stress. PD model combining many of the PD mechanisms could allow robust and relevant platform for drug development.

Method: aSyn aggregation was induced in neurons using aSyn pre-formed fibrils (PFFs), which seed recruitment and misfolding of endogenous aSyn to form aggregates of serine129-phosphorylated aSyn (paSyn). The neurons were then exposed to another stressor to induce oxidative stress and further cause the degeneration of dopamine neurons. The neurodegeneration was estimated by the numbers of surviving dopamine neurons, and as motor defects in mice. Also, the percentage of dopamine neurons containing paSyn aggregates was analysed to evaluate the extent occurrence of LB-like inclusions.

Results: In this study, we successfully obtained the first set of data for the novel model of PD. The addition of PFF, followed by another stressor led to occurrence of paSyn aggregates, and extensive loss of dopamine neurons in substantia nigra and their axons in striatum . The behavioural data from mice were inconclusive, suggesting the need for more sensitive behavioural tests for this model.

Conclusion: We conclude that the novel model holds the potential to form a robust platform for PD research and drug development. The preliminary data implies the need for further optimization of the stressor concentration, and selection of tests for motor defects most suited for this model.

« Back to MDS Virtual Congress 2020

MDS Abstracts - https://www.mdsabstracts.org/abstract/characterization-of-novel-alpha-synuclein-aggregation-model-of-parkinsons-disease/