Propagation of α-Synuclein Strains within Human Reconstructed Neuronal Network.

Abstract:

:Reappraisal of neuropathological studies suggests that pathological hallmarks of Alzheimer's disease and Parkinson's disease (PD) spread progressively along predictable neuronal pathways in the human brain through unknown mechanisms. Although there is much evidence supporting the prion-like propagation and amplification of α-synuclein (α-Syn) in vitro and in rodent models, whether this scenario occurs in the human brain remains to be substantiated. Here we reconstructed in microfluidic devices corticocortical neuronal networks using human induced pluripotent stem cells derived from a healthy donor. We provide unique experimental evidence that different strains of human α-Syn disseminate in "wild-type" human neuronal networks in a prion-like manner. We show that two distinct α-Syn strains we named fibrils and ribbons are transported, traffic between neurons, and trigger to different extents, in a dose- and structure-dependent manner, the progressive accumulation of PD-like pathological hallmarks. We further demonstrate that seeded aggregation of endogenous soluble α-Syn affects synaptic integrity and mitochondria morphology.

journal_name

Stem Cell Reports

journal_title

Stem cell reports

authors

Gribaudo S,Tixador P,Bousset L,Fenyi A,Lino P,Melki R,Peyrin JM,Perrier AL

doi

10.1016/j.stemcr.2018.12.007

subject

Has Abstract

pub_date

2019-02-12 00:00:00

pages

230-244

issue

2

issn

2213-6711

pii

S2213-6711(18)30526-5

journal_volume

12

pub_type

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