title: Neuron-to-neuron transmission of α-synuclein fibrils through axonal transport.
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 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Departments of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305-5402, USA.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Freundt
authors.forename: Nate
authors.initials: N
authors.lastname: Maynard
authors.forename: Eileen K
authors.initials: EK
authors.lastname: Clancy
authors.forename: Shyamali
authors.initials: S
authors.lastname: Roy
authors.forename: Luc
authors.initials: L
authors.lastname: Bousset
authors.forename: Yannick
authors.initials: Y
authors.lastname: Sourigues
authors.forename: Markus
authors.initials: M
authors.lastname: Covert
authors.forename: Ronald
authors.initials: R
authors.lastname: Melki
authors.forename: Karla
authors.initials: K
authors.lastname: Kirkegaard
authors.forename: Michel
authors.initials: M
authors.lastname: Brahic
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001370:Axonal Transport / Q000502:physiology*; D005456:Fluorescent Dyes; D007150:Immunohistochemistry; D008301:Maleimides; D051379:Mice; D046210:Microfluidic Analytical Techniques; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D009454:Neurofibrils / Q000502:physiology*; D009457:Neuroglia / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D010446:Peptide Fragments / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*; D051844:alpha-Synuclein / Q000502:physiology*
chemical_list: C504424:Alexa Fluor 488 C5-maleimide; D016229:Amyloid beta-Peptides; D005456:Fluorescent Dyes; D008301:Maleimides; D010446:Peptide Fragments; D051844:alpha-Synuclein; C075222:amyloid beta-protein (1-42)