The expression level of alpha-synuclein in different neuronal populations is the primary determinant of its prion-like seeding

Josquin Courte (1) , Luc Bousset (2) , Ysander von Boxberg (1) , Catherine Villard (3) , Ronald Melki (2) , Jean-Michel Peyrin (1)

1 NPS - Neuroscience Paris Seine
2 LMN - Laboratoire des Maladies Neurodégénératives - UMR 9199
3 PCC - Laboratoire Physico-Chimie Curie [Institut Curie]

Alpha-synuclein (aSyn)-rich aggregates propagate in neuronal networks and compromise cellular homeostasis leading to synucleinopathies such as Parkinson's disease. Aggregated aSyn spread follows a conserved spatio-temporal pattern that is not solely dependent on connectivity. Hence, the differential tropism of aSyn-rich aggregates to distinct brain regions, or their ability to amplify within those regions, must contribute to this process. To better understand what underlies aSyn-rich aggregates distribution within the brain, we generated primary neuronal cultures from various brain regions of wild-type mice and mice expressing a reduced level of aSyn, and exposed them to fibrillar aSyn. We then assessed exogenous fibrillar aSyn uptake, endogenous aSyn seeding, and endogenous aSyn physiological expression levels. Despite a similar uptake of exogenous fibrils by neuronal cells from distinct brain regions, the seeded aggregation of endogenous aSyn differed greatly from one neuronal population to another. The different susceptibility of neuronal populations was linked to their aSyn expression level. Our data establish that endogenous aSyn expression level plays a key role in fibrillar aSyn prion-like seeding, supporting that endogenous aSyn expression level participates in selective regional brain vulnerability.

Domaines: Biochimie [q-bio.BM]; Biologie cellulaire; Neurobiologie

Josquin Courte, Luc Bousset, Ysander von Boxberg, Catherine Villard, Ronald Melki, et al.. The expression level of alpha-synuclein in different neuronal populations is the primary determinant of its prion-like seeding. Scientific Reports, 2020, 10, pp.4895. ⟨10.1038/s41598-020-61757-x⟩. ⟨cea-02511811⟩