Neuron‐to‐neuron transmission of α‐synuclein fibrils through axonal transport

EC Freundt, N Maynard, EK Clancy, S Roy… - Annals of …, 2012 - Wiley Online Library
EC Freundt, N Maynard, EK Clancy, S Roy, L Bousset, Y Sourigues, M Covert, R Melki
Annals of neurology, 2012Wiley Online Library
Abstract Objective: The lesions of Parkinson disease spread through the brain in a
characteristic pattern that corresponds to axonal projections. Previous observations suggest
that misfolded α‐synuclein could behave as a prion, moving from neuron to neuron and
causing endogenous α‐synuclein to misfold. Here, we characterized and quantified the
axonal transport of α‐synuclein fibrils and showed that fibrils could be transferred from
axons to second‐order neurons following anterograde transport. Methods: We grew primary …
Objective
The lesions of Parkinson disease spread through the brain in a characteristic pattern that corresponds to axonal projections. Previous observations suggest that misfolded α‐synuclein could behave as a prion, moving from neuron to neuron and causing endogenous α‐synuclein to misfold. Here, we characterized and quantified the axonal transport of α‐synuclein fibrils and showed that fibrils could be transferred from axons to second‐order neurons following anterograde transport.
Methods
We grew primary cortical mouse neurons in microfluidic devices to separate somata from axonal projections in fluidically isolated microenvironments. We used live‐cell imaging and immunofluorescence to characterize the transport of fluorescent α‐synuclein fibrils and their transfer to second‐order neurons.
Results
Fibrillar α‐synuclein was internalized by primary neurons and transported in axons with kinetics consistent with slow component‐b of axonal transport (fast axonal transport with saltatory movement). Fibrillar α‐synuclein was readily observed in the cell bodies of second‐order neurons following anterograde axonal transport. Axon‐to‐soma transfer appeared not to require synaptic contacts.
Interpretation
These results support the hypothesis that the progression of Parkinson disease can be caused by neuron‐to‐neuron spread of α‐synuclein aggregates and that the anatomical pattern of progression of lesions between axonally connected areas results from the axonal transport of such aggregates. That the transfer did not appear to be trans‐synaptic gives hope that α‐synuclein fibrils could be intercepted by drugs during the extracellular phase of their journey. ANN NEUROL 2012;72:517–524
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