Intracellular accumulation of a-synuclein (a-syn) and formation of Lewy bodies are neuropathological characteristics of Parkinson's disease (PD) and related a-synucleinopathies. Oligomerization and spreading of a-syn from neuron to neuron have been suggested as key events contributing to the progression of PD. To directly visualize and characterize a-syn oligomerization and spreading in vivo, we generated two independent conditional transgenic mouse models based on a-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 a-syn oligomers in vivo. Using these mouse models, we demonstrate an age-dependent accumulation of a specific subtype of a-syn oligomers. We provide in vivo evidence that, although a-syn is found throughout neurons, a-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.

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l‐DOPA‐induced dyskinesia is characterised by debilitating involuntary movement, which limits quality of life in patients suffering from Parkinson’s disease. Here, we investigate effects of the α2 adrenoceptor antagonist idazoxan on l‐DOPA‐induced dyskinesia as well as on alterations of extracellular l‐DOPA and dopamine (DA) levels in the striatum in dyskinetic rats. Male Wistar rats were unilaterally lesioned with 6‐hydroxydopamine and subsequently treated with l‐DOPA/benserazide to induce stable dyskinetic movements. Administration of idazoxan [(9 mg/kg, intraperitoneal (i.p.)] significantly alleviated l‐DOPA‐induced dyskinesia, whereas idazoxan (3 mg/kg, i.p.) did not affect dyskinetic behaviour. Bilateral in vivo microdialysis revealed that idazoxan 9 mg/kg reduces extracellular peak l‐DOPA levels in the lesioned and intact striatum as well as DA levels in the lesioned striatum. In parallel, the exposure to idazoxan in the striatum was monitored. Furthermore, no idazoxan and l‐DOPA drug–drug interaction was found in plasma, brain tissue and CSF. In conclusion, the decrease of l‐DOPA‐derived extracellular DA levels in the lesioned striatum significantly contributes to the anti‐dyskinetic effect of idazoxan.

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