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

Abstract

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.

Prion-Like Propagation of Protein Aggregation and Related Therapeutic Strategies

“…The kinetics of movement were consistent with slow component-b transport along the axon, rather than diffusion. These results support the idea that α-synuclein can be transported anterograde, released, and spread to second order neurons trans-synaptically [65]. However, the role of synaptic activity in this type of transfer is unknown.…”

The dementia-associated APOE ε4 allele is not associated with rapid eye movement sleep behavior disorder

“…It is possible that stochastic events, or other genetic or environmental factors, determine whether -synuclein will first be deposited in brain areas associated with dementia and later in the areas associated with parkinsonism, or vice versa (Lai, et al, 2008,Lai andSiegel, 2003). The observation that -synuclein can spread in the brain in a prion-like fashion (Bernis, et al, 2015,Danzer, et al, 2009,Freundt, et al, 2012 may support a stochastic progression hypothesis, yet additional neuropathological studies are needed to examine this possibility. Therefore, there are two possible explanations for the lack of association between the APOE 4 allele and conversion to DLB in our cohort.…”

Striatal Blood–Brain Barrier Permeability in Parkinson'S Disease

“…1 This is conceivable within the paradigm of retrograde (axon terminal to soma) Lewy pathology spread. 2,3 Almost all regions affected in Braak stage 1 have axon terminals outside the blood-brain barrier (BBB). That same BBB, however, protects the higher-order regions, whose axon terminals reside within the central nervous system, from blood-borne substances.…”