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 Reportsjournal_title
Stem cell reportsauthors
Gribaudo S,Tixador P,Bousset L,Fenyi A,Lino P,Melki R,Peyrin JM,Perrier ALdoi
10.1016/j.stemcr.2018.12.007subject
Has Abstractpub_date
2019-02-12 00:00:00pages
230-244issue
2issn
2213-6711pii
S2213-6711(18)30526-5journal_volume
12pub_type
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