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

Josquin Courte,Ronald Melki,Catherine Villard,Jean-Michel Peyrin,Ysander Von Boxberg,Luc Bousset

doi:10.1038/s41598-020-61757-x

Abstract

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.

Highlights

Alpha-synuclein-rich aggregates propagate in neuronal networks and compromise cellular homeostasis leading to synucleinopathies such as Parkinson’s disease
ASyn is abundantly expressed in neurons[1], and mostly localizes at synapses where it regulates presynaptic vesicles turnover2. aSyn is a constituent of Lewy bodies and neurites[3], named Lewy pathology (LP), the hallmarks of a group of neurodegenerative diseases named synucleinopathies that comprise Parkinson’s disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB)[4,5]
We report that aSyn expression level and sub-cellular localization differ in neurons of different origins, and that the differences we observe correlate with exogenous aSyn Fibrils seeding propensity within those neurons

Summary

Introduction

Alpha-synuclein (aSyn)-rich aggregates propagate in neuronal networks and compromise cellular homeostasis leading to synucleinopathies such as Parkinson’s disease. 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. We report that aSyn expression level and sub-cellular localization differ in neurons of different origins, and that the differences we observe correlate with exogenous aSyn Fibrils seeding propensity within those neurons. To strengthen this finding, we selectively decreased aSyn expression level in Hip neurons by crossbreeding WT and SNCA−/− mice to generate SNCA+/− heterozygous embryos. Our data suggest that the expression level of aSyn is a key element in aSyn prion-like seeding, and might strongly impact the pattern of LP development in heterogeneous neural networks

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