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Modelling α-Synuclein Aggregation and Neurodegeneration with Fibril Seeds in Primary Cultures of Mouse Dopaminergic Neurons

Abstract : To model α-Synuclein (αS) aggregation and neurodegeneration in Parkinson’s disease (PD), we established cultures of mouse midbrain dopamine (DA) neurons and chronically exposed them to fibrils 91 (F91) generated from recombinant human αS. We found that F91 have an exquisite propensity to seed the aggregation of endogenous αS in DA neurons when compared to other neurons in midbrain cultures. Until two weeks post-exposure, somal aggregation in DA neurons increased with F91 concentrations (0.01–0.75 μM) and the time elapsed since the initiation of seeding, with, however, no evidence of DA cell loss within this time interval. Neither toxin-induced mitochondrial deficits nor genetically induced loss of mitochondrial quality control mechanisms promoted F91-mediated αS aggregation or neurodegeneration under these conditions. Yet, a significant loss of DA neurons (~30%) was detectable three weeks after exposure to F91 (0.5 μM), i.e., at a time point where somal aggregation reached a plateau. This loss was preceded by early deficits in DA uptake. Unlike αS aggregation, the loss of DA neurons was prevented by treatment with GDNF, suggesting that αS aggregation in DA neurons may induce a form of cell death mimicking a state of trophic factor deprivation. Overall, our model system may be useful for exploring PD-related pathomechanisms and for testing molecules of therapeutic interest for this disorder
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https://hal.archives-ouvertes.fr/hal-03679039
Contributor : Patrick Pierre Michel Connect in order to contact the contributor
Submitted on : Wednesday, May 25, 2022 - 5:51:14 PM
Last modification on : Monday, May 30, 2022 - 11:58:08 AM

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Aurore Tourville, David Akbar, Olga Corti, Jochen Prehn, Ronald Melki, et al.. Modelling α-Synuclein Aggregation and Neurodegeneration with Fibril Seeds in Primary Cultures of Mouse Dopaminergic Neurons. Cells, MDPI, 2022, 11 (10), pp.1640. ⟨10.3390/cells11101640⟩. ⟨hal-03679039⟩

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