Modeling Parkinson's Disease Neuropathology and Symptoms by Intranigral Inoculation of Preformed Human α-Synuclein Oligomers

The accumulation of aggregated alpha-synuclein (alpha Syn) is a hallmark of Parkinson's disease (PD). Current evidence indicates that small soluble alpha Syn oligomers (alpha SynOs) are the most toxic species among the forms of alpha Syn aggregates, and that size and topological structural properties are crucial factors for alpha SynOs-mediated toxicity, involving the interaction with either neurons or glial cells. We previously characterized a human alpha SynO (H-alpha SynO) with specific structural properties promoting toxicity against neuronal membranes. Here, we tested the neurotoxic potential of these H-alpha SynOs in vivo, in relation to the neuropathological and symptomatic features of PD. The H-alpha SynOs were unilaterally infused into the rat substantia nigra pars compacta (SNpc). Phosphorylated alpha Syn (p129-alpha Syn), reactive microglia, and cytokine levels were measured at progressive time points. Additionally, a phagocytosis assay in vitro was performed after microglia pre-exposure to alpha synOs. Dopaminergic loss, motor, and cognitive performances were assessed. H-alpha SynOs triggered p129-alpha Syn deposition in SNpc neurons and microglia and spread to the striatum. Early and persistent neuroinflammatory responses were induced in the SNpc. In vitro, H-alpha SynOs inhibited the phagocytic function of microglia. H-alpha synOs-infused rats displayed early mitochondrial loss and abnormalities in SNpc neurons, followed by a gradual nigrostriatal dopaminergic loss, associated with motor and cognitive impairment. The intracerebral inoculation of structurally characterized H-alpha SynOs provides a model of progressive PD neuropathology in rats, which will be helpful for testing neuroprotective therapies.