Advances in modelling alpha-synuclein-induced Parkinson's diseases in rodents: Virus-based models versus inoculation of exogenous preformed toxic species

Aggregates of alpha-synuclein (?Syn) have been described in Parkinson's disease (PD) patients, and recent evidence has suggested that the most toxic ?Syn species in PD are small soluble aggregates including oligomers, prefibrils, protofibrils. The physiological function of ?Syn is still highly debated, with a possible role in synaptic vesicle trafficking and release at the presynaptic compartment, and in the regulation of gene expression in the nucleus. Emerging evidence indicate that most of ?Syn functions are related with the crucial ability to bind biological membranes, which is associated with structural conversion from a disordered monomer to an ?-helical enriched structure. Conformational properties of ?Syn can be modulated by a number of factors including post-translational modifications, gene duplication and triplication-driven overexpression, single point mutations, environmental changes, which affect membrane binding and the protein propensity to aggregate in toxic species. The recognized toxic role of ?Syn in PD has laid the rational for purposing of ?Syn-based, neuropathologically relevant preclinical models of PD. Different approaches have led to the establishment of transgenic models, viral vector-based models, and more recently models based on the intracerebral inoculation of exogenous ?Syn preformed fibrils/oligomers. Here, we overview and compare viral vector-based models of ?Syn overexpression and models obtained by direct intracerebral infusion of in vitro preformed ?Syn species. The advantages and pitfalls associated with these different approaches are discussed.