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Stem Cell Reports. 2019 Feb 12;12(2):230-244. doi: 10.1016/j.stemcr.2018.12.007. Epub 2019 Jan 10.

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

Author information

1
INSERM U861, I-STEM, AFM, Corbeil-Essonnes 91100, France; UEVE U861, I-STEM, AFM, Corbeil-Essonnes 91100, France.
2
Sorbonne Universités, Faculté des Sciences et Ingénierie, CNRS/UMR 8256, B2A, Biological Adaptation and Ageing, Institut de Biologie Paris Seine, Paris 75005, France.
3
Laboratory of Neurodegenerative Disease, Institut François Jacob, MIRCen, CEA-CNRS, Fontenay aux Roses 92265, France.
4
Laboratory of Neurodegenerative Disease, Institut François Jacob, MIRCen, CEA-CNRS, Fontenay aux Roses 92265, France. Electronic address: ronald.melki@cnrs.fr.
5
Sorbonne Universités, Faculté des Sciences et Ingénierie, CNRS/UMR 8256, B2A, Biological Adaptation and Ageing, Institut de Biologie Paris Seine, Paris 75005, France. Electronic address: jean-michel.peyrin@upmc.fr.
6
INSERM U861, I-STEM, AFM, Corbeil-Essonnes 91100, France; UEVE U861, I-STEM, AFM, Corbeil-Essonnes 91100, France. Electronic address: anselme.perrier@inserm.fr.

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.

KEYWORDS:

Lewy body; Parkinson's disease; human cortical neuron; human pluripotent stem cells; microfluidic; neuronal dysfunction; nucleation; prion-like; synuclein

PMID:
30639210
DOI:
10.1016/j.stemcr.2018.12.007
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