Propagation of α-Synuclein Strains within Human Reconstructed Neuronal Network

Summary: 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. : In this article, Gribaudo and colleagues report the internalization and trafficking of exogenous α-synuclein fibrils and ribbons through fluidically isolated cortical networks derived from wild-type human iPSCs. These assemblies trigger via seeding mechanisms the accumulation of endogenous phosphorylated α-synuclein, in a structure-, dose-, and time-dependent manner. Phosphorylated α-Syn structures resist degradation and accumulate in the cytoplasm of neurons, affecting Ca2+ homeostasis and mitochondria morphology. Keywords: human pluripotent stem cells, Parkinson's disease, microfluidic, prion-like, nucleation, synuclein, Lewy body, human cortical neuron, neuronal dysfunction