Propagation of α-Synuclein Strains within Human Reconstructed Neuronal Network

Abstract

SummaryReappraisal 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.

Back and to the Future: From Neurotoxin‐Induced to Human Parkinson's Disease Models

“…Peelaerts et al (2015) also reported that another insoluble form of recombinant α-synuclein, named ribbons, cause rather Lewy neurite-like filamentous phenotype, while fibrils demonstrated the highest neurotoxic potential. To contrast, Gribaudo et al (2019) assessing propagation of fibrils and ribbons in humanderived neurons demonstrated that both ribbons and fibrils form similar inclusions that persist over time and are transferred between neurons. Both strains have no effect on cell viability or morphology, but alterations in Ca 2+ homeostasis with progression of α-synuclein aggregation and altered mitochondrial morphology were recorded.…”

“…To contrast, Gribaudo et al. () assessing propagation of fibrils and ribbons in human‐derived neurons demonstrated that both ribbons and fibrils form similar inclusions that persist over time and are transferred between neurons. Both strains have no effect on cell viability or morphology, but alterations in Ca 2+ homeostasis with progression of α‐synuclein aggregation and altered mitochondrial morphology were recorded.…”

“…Different species of α‐synuclein were proposed to cause different synucleinopathies, and therefore, were used as a model of α‐synuclein pathology. α‐synuclein monomers and oligomers were shown to cause protein aggregation neither in vitro nor in vivo despite spreading more efficiently than insoluble α‐synuclein species (Gribaudo et al., ; Luk et al., ; Peelaerts et al., ). Peelaerts et al.…”

“…Different species of α-synuclein were proposed to cause different synucleinopathies, and therefore, were used as a model of α-synuclein pathology. α-synuclein monomers and oligomers were shown to cause protein aggregation neither in vitro nor in vivo despite spreading more efficiently than insoluble α-synuclein species (Gribaudo et al, 2019;Luk et al, 2009;Peelaerts et al, 2015). Peelaerts et al (2015) also reported that another insoluble form of recombinant α-synuclein, named ribbons, cause rather Lewy neurite-like filamentous phenotype, while fibrils demonstrated the highest neurotoxic potential.…”

α‐synuclein oligomers and fibrils: a spectrum of species, a spectrum of toxicities

“…(Flavin et al ). α‐syn fibrillar assemblies also trigger neurodegeneration through chronic inflammation (Gustot et al ; Hoffmann et al ; Peralta Ramos et al ; Gribaudo et al ).…”