Summary: Intracellular accumulation of α-synuclein (α-syn) and formation of Lewy bodies are neuropathological characteristics of Parkinson’s disease (PD) and related α-synucleinopathies. Oligomerization and spreading of α-syn from neuron to neuron have been suggested as key events contributing to the progression of PD. To directly visualize and characterize α-syn oligomerization and spreading in vivo, we generated two independent conditional transgenic mouse models based on α-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 α-syn oligomers in vivo. Using these mouse models, we demonstrate an age-dependent accumulation of a specific subtype of α-syn oligomers. We provide in vivo evidence that, although α-syn is found throughout neurons, α-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 α-syn oligomers in vivo. : Kiechle et al. present two transgenic mouse models that allow direct quantitative and spatial detection of α-synuclein (α-syn) oligomers in vivo. They demonstrate α-syn aggregation at the synapse, age-dependent accumulation of 8–16-mer α-syn oligomer species, and trans-cellular oligomer spreading from forebrain to hindbrain neurons. Keywords: Parkinson's disease, transgenic mouse model, alpha-synuclein, oligomerization, synaptic oligomers, aging, neurodegeneration, progressive phenotype, spreading, protein-fragment complementation
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