α-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells.

By C. Hansen, Elodie Angot, A. Bergström, Jennifer A. Steiner, Laura Pieri, G. Paul, T. Outeiro, R. Melki, P. Kallunki, Karina Fog and 2 more. Journal of Clinical Investigation, 2011

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Post-mortem analyses of brains from patients with Parkinson disease who received fetal mesencephalic transplants show that α-synuclein-containing (α-syn-containing) Lewy bodies gradually appear in grafted neurons. Here, we explored whether intercellular transfer of α-syn from host to graft, followed by seeding of α-syn aggregation in recipient neurons, can contribute to this phenomenon. We assessed α-syn cell-to-cell transfer using microscopy, flow cytometry, and high-content screening in several coculture model systems. Coculturing cells engineered to express either GFP- or DsRed-tagged α-syn resulted in a gradual increase in double-labeled cells. Importantly, α-syn-GFP derived from 1 neuroblastoma cell line localized to red fluorescent aggregates in other cells expressing DsRed-α-syn, suggesting a seeding effect of transmitted α-syn. Extracellular α-syn was taken up by cells through endocytosis and interacted with intracellular α-syn. Next, following intracortical injection of recombinant α-syn in rats, we found neuronal uptake was attenuated by coinjection of an endocytosis inhibitor. Finally, we demonstrated in vivo transfer of α-syn between host cells and grafted dopaminergic neurons in mice overexpressing human α-syn. In summary, intercellularly transferred α-syn interacts with cytoplasmic α-syn and can propagate α-syn pathology. These results suggest that α-syn propagation is a key element in the progression of Parkinson disease pathology.

Subfields: Cellular and Molecular Neuroscience, Neurology

View Paper: https://www.semanticscholar.org/paper/134dd480c2ba6dbcee67fd57cc8ad36fb2f90061

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Citations in the corpus

α-Synuclein in Parkinson's disease. (2012, background): “…incorporated host a-synuclein in their cell soma (Desplats et al. 2009), and fetal dopaminergic neurons also showed uptake of hosta-synuclein (Hansen et al. 2011); on the other, fetal dopaminergic grafts in humans showed LB pathology many years after implantation, although whether the…”
Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice (2012, background): “However, although cell–cell transfer of soluble Syn within the CNS has been reported (Desplats et al., 2009; Danzer et al., 2011; Hansen et al., 2011), the transmission of pathological Syn species and its potential role in the pathogenesis of DLB/ PD and related synucleinopathies remain largely…”
Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats (2014, methodology): “On day four of differentiation, cells were transiently transfected using Lipofectamine 2000 (Life technologies) with plasmids expressing bimolecular fluorescence complementation (BiFC) vectors of truncated (N- or C-terminus), full-length Venus fused to human wildtype α-synuclein [15], Venus alone (k”
Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds (2013, background): “(2007) beta-Sheet structured beta-amyloid(1-40) perturbs phosphatidylcholine model membranes.”
Exogenous α-Synuclein Fibrils Induce Lewy Body Pathology Leading to Synaptic Dysfunction and Neuron Death (2011, positive): “…of intracellular soluble proteins into inclusions, (Clavaguera et al., 2009; Desplats et al., 2009; Frost et al., 2009; Guo and Lee, 2011; Hansen et al. 2011; Luk et al., 2009), they either employed additional factors to assist the entry of the fibrils into cells, or they utilized cell…”
Mitochondrial dysfunction in Parkinson's disease: molecular mechanisms and pathophysiological consequences (2012, neutral): “…diffusion, endocytosis, and exosome-mediated uptake have been observed, and it is highly likely that the mode of cell entry depends on the type of a -synuclein species to be taken up (Sung et al , 2001; Desplats et al , 2009; Park et al , 2009; Emmanouilidou et al , 2010; Hansen et al , 2011).”
Predicting regional neurodegeneration from the healthy brain functional connectome. (2012, background): “Providing a more parsimonious account, growing evidence suggests that prion-like mechanisms may promote the spread of toxic, misfolded, nonprion protein species between interconnected neurons (Baker et al., 1993, 1994; Brundin et al., 2010; Clavaguera et al., 2009; Frost and Diamond, 2010; Frost et ”