In vivo models of alpha-synuclein transmission and propagation

The abnormal accumulation of alpha-synuclein aggregates in neurons, nerve fibers, or glial cells is the hallmark of a group of neurodegenerative diseases known collectively as alpha-synucleinopathies. Clinical, neuropathological, and experimental evidence strongly suggests that alpha-synuclein plays a role not only as a trigger of pathological processes at disease inception, but also as a mediator of pathological spreading during disease progression. Specific properties of alpha-synuclein, such as its ability to pass from one neuron to another, its tendency to aggregate, and its potential to generate self-propagating species, have been described and elucidated in animal models and may contribute to the relentless exacerbation of Parkinson's disease pathology in patients. Animal models used for studying alpha-synuclein accumulation, aggregation, and propagation are mostly based on three approaches: (1) intra-parenchymal inoculations of exogenous alpha-synuclein (e.g., synthetic alpha-synuclein fibrils), (2) transgenic mice, and (3) animals (mice or rats) in which alpha-synuclein overexpression is induced by viral vector injections. Whereas pathological alpha-synuclein changes are consistently observed in these models, important differences are also found. In particular, pronounced pathology in transgenic mice and viral vector-injected animals does not appear to involve self-propagating alpha-synuclein species. A critical discussion of these models reveals their strengths and limitations and provides the basis for recommendations concerning their use for future investigations.