Neuron-to-neuron transmission of α-synuclein fibrils through axonal transport
Published Date:Oct 2012
Source:Ann Neurol. 72(4):517-524.
Pubmed Central ID:PMC3490229
Funding:1F32GM090545/GM/NIGMS NIH HHS/United States
5R00CA125994/CA/NCI NIH HHS/United States
AI-65972/AI/NIAID NIH HHS/United States
DP1 827/DP/NCCDPHP CDC HHS/United States
DP1 OD000827/OD/NIH HHS/United States
R00 CA125994/CA/NCI NIH HHS/United States
R01 AI065972/AI/NIAID NIH HHS/United States
The lesions of Parkinson's 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.
We grew primary cortical mouse neurons in microfluidic devices to separate soma 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.
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.
These results support the hypothesis that the progression of Parkinson's 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 transsynaptic gives hope that α-synuclein fibrils could be intercepted by drugs during the extra-cellular phase of their journey.
image/gif image/jpeg image/gif image/jpeg image/gif image/jpeg image/gif image/jpeg text/plain application/pdf video/mp4 video/mp4
You May Also Like: