Combining fibril‐induced alpha‐synuclein aggregation and 6‐hydroxydopamine in a mouse model of Parkinson's disease and the effect of cerebral dopamine neurotrophic factor on the induced neurodegeneration

Abstract

The existent pre‐clinical models of Parkinson's disease do not simultaneously recapitulate severe degeneration of dopamine neurons and the occurrence of alpha‐synuclein (aSyn) aggregation in one study system. In this study, we injected aSyn pre‐formed fibrils (PFF) and 6‐hydroxydopamine (6‐OHDA) unilaterally into the striatum of C57BL/6 wild‐type male mice at an interval of 2 weeks to induce aggregation of aSyn protein and trigger the loss of dopamine neurons simultaneously in one model and studied the behavioural effects of the combination in these mice. 6‐OHDA was tested at three different doses, and 2 μg of 6‐OHDA combined with PFF‐induced aSyn aggregation was found to produce the most optimal disease phenotype. At 14 weeks timepoint, mice injected with a combination of PFF and 6‐OHDA sustained significant damage to the nigrostriatal pathway and exhibited aSyn‐positive aggregation. Our data suggest that the neurons that formed large aSyn aggregates were particularly vulnerable to 6‐OHDA‐induced degeneration. We also demonstrate the manifestation of a relatively aggressive pathology in 2‐ to 4‐month‐old mice, as compared to younger 7‐ to 9‐week‐old ones. Furthermore, cerebral dopamine neurotrophic factor (CDNF) administered intrastriatally rescued dopamine neurons and motor behaviour of the animals to some extent from 6‐OHDA toxicity. However, no such effect could be seen in the novel 6‐OHDA + PFFs combination model. For the first time, we demonstrate the combined effect of PFF and 6‐OHDA simultaneously in one model. We further discuss the scope for further optimizing this combination model to develop it as a promising pre‐clinical platform for drug screening and development.