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.
Highlights
Chronic neurodegenerative diseases are tightly linked to the progressive accumulation of abnormally folded protein conformers inside or outside neurons
These abnormal conformers are proposed to mediate neuronal dysfunctions. In synucleinopathies such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), a-synuclein (a-Syn), a presynaptic protein involved in the regulation of synaptic vesicle release, accumulates in a phosphorylated and insoluble form in neurons
This, together with the observation that Lewy bodies are detected in neurons grafted in PD patients (Kordower et al, 2008; Li et al, 2008), suggests that neuropathological hallmarks spread from diseased to naive neurons through unknown mechanisms
Summary
Chronic neurodegenerative diseases are tightly linked to the progressive accumulation of abnormally folded protein conformers inside or outside neurons. These abnormal conformers are proposed to mediate neuronal dysfunctions. In synucleinopathies such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), a-synuclein (a-Syn), a presynaptic protein involved in the regulation of synaptic vesicle release, accumulates in a phosphorylated and insoluble form in neurons. As in Alzheimer’s disease (Braak et al, 2006), PD/DLB/MSA pathological hallmarks progress spatially and temporally in the brains of affected patients (Braak et al, 2003b). This, together with the observation that Lewy bodies are detected in neurons grafted in PD patients (Kordower et al, 2008; Li et al, 2008), suggests that neuropathological hallmarks spread from diseased to naive neurons through unknown mechanisms
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