Oligodendrocytes may provide the extra density of α-synuclein filaments from multiple system atrophy

Abstract

Prion-like templated seeding of a-synuclein filaments is thought to underlie the spreading of multiple system atrophy (MSA) and other synucleinopathies through the brain. Here, we used -synuclein filaments extracted from the brains of individuals with MSA to induce seeded aggregation in undifferentiated human neuroblastoma SH-SY5Y cells, human iNeurons, mixed primary murine cortical cells and murine oligodendrocyte-enriched primary cultures, all overexpressing human -synuclein, followed by determination of the cryo-EM structures of the seeded filaments. Whereas MSA seeds comprise two protofilaments with an unidentified non-proteinaceous density located between protofilaments, seeding resulted in the formation of filaments with a single protofilament. Only the seeded structures derived from oligodendrocytes contained an extra density that resembled that of the seeds. This suggests that oligodendrocytes may provide the chemical component that is responsible for the extra density at the protofilament interface of MSA filaments. In support, the injection of MSA seeds into the striatum of transgenic mice expressing human -synuclein under the control of the oligodendrocyte-specific proteolipid protein promoter, also yielded seeded filaments with a single protofilament and a similar extra density.