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

Details

• Alternative Title:
  Ann Neurol
• Personal Author:
  Freundt, Eric C. ; Maynard, Nate ; Clancy, Eileen K. ; Roy, Shyamali ; Bousset, Luc ; Sourigues, Yannick ; Covert, Markus ; Melki, Ronald ; Kirkegaard, Karla ; Brahic, Michel
• Description:
  Objective
  
  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.
  
  Methods
  
  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.
  
  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'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.
  
  
• Subjects:
  Alpha-Synuclein Amyloid Beta-Peptides Animals Article Axonal Transport Fluorescent Dyes Immunohistochemistry Maleimides Mice Microfluidic Analytical Techniques Microscopy, Confocal Microscopy, Fluorescence Neurofibrils Neuroglia Neurons Peptide Fragments Synaptic Transmission

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• Source:
  Ann Neurol. 72(4):517-524
• Pubmed ID:
  23109146
• Pubmed Central ID:
  PMC3490229
• Document Type:
  Journal Article
• Funding:
  R01 AI065972/AI/NIAID NIH HHSUnited States/ ; R00 CA125994/CA/NCI NIH HHSUnited States/ ; DP1 827/DP/NCCDPHP CDC HHSUnited States/ ; F32 GM090545/GM/NIGMS NIH HHSUnited States/ ; DP1 OD000827/OD/NIH HHSUnited States/ ; AI-65972/AI/NIAID NIH HHSUnited States/ ; 5R00CA125994/CA/NCI NIH HHSUnited States/ ; 1F32GM090545/GM/NIGMS NIH HHSUnited States/
• Volume:
  72
• Issue:
  4
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:00e96ebd2cc2c0bcf9e9b49df598f5f74cef329e3f7249b638a07ede591a6ad3
• Download URL:
  https://stacks.cdc.gov/view/cdc/33462/cdc_33462_DS1.pdf
• File Type:
  [PDF - 1.64 MB ]