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Modelling $\alpha$-synuclein aggregation and neurodegeneration with fibril seeds in primary cultures of mouse dopaminergic neurons

Abstract : To model $\alpha$-Synuclein ($\alpha$S) 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 $\alpha$S. We found that F91 have an exquisite propensity to seed the aggregation of endogenous $\alpha$S 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 $\alpha$S 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 $\alpha$S 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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Contributor : Ronald Melki Connect in order to contact the contributor
Submitted on : Tuesday, May 31, 2022 - 7:26:23 PM
Last modification on : Saturday, September 3, 2022 - 3:33:08 AM


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Aurore Tourville, David Akbar, Olga Corti, Jochen H. M. Prehn, Ronald Melki, et al.. Modelling $\alpha$-synuclein aggregation and neurodegeneration with fibril seeds in primary cultures of mouse dopaminergic neurons. Cells, MDPI, 2022, 11 (10), pp.1640. ⟨10.3390/cells11101640⟩. ⟨cea-03683729⟩



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