In Vivo Protein Complementation Demonstrates Presynaptic α-Synuclein Oligomerization and Age-Dependent Accumulation of 8-16-mer Oligomer Species

Intracellular accumulation of alpha-synuclein (alpha-syn) and formation of Lewy bodies are neuropathological characteristics of Parkinson's disease (PD) and related alpha-synucleinopathies. Oligomerization and spreading of alpha-syn from neuron to neuron have been suggested as key events contributing to the progression of PD. To directly visualize and characterize alpha-syn oligomerization and spreading in vivo, we generated two independent conditional transgenic mouse models based on alpha-syn protein complementation assays using neuron-specifically expressed split Gaussia luciferase or split Venus yellow fluorescent protein (YFP). These transgenic mice allow direct assessment of the quantity and subcellular distribution of alpha-syn oligomers in vivo. Using these mouse models, we demonstrate an age-dependent accumulation of a specific subtype of alpha-syn oligomers. We provide in vivo evidence that, although alpha-syn is found throughout neurons, alpha-syn oligomerization takes place at the presynapse. Furthermore, our mouse models provide strong evidence for a transsynaptic cell-to-cell transfer of de novo generated a-syn oligomers in vivo.