Quaternary structure of patient-homogenate amplified α-synuclein fibrils modulates seeding of endogenous α-synuclein

Abstract

Parkinson's disease (PD) and Multiple System Atrophy (MSA) are progressive and unremitting neurological diseases that are neuropathologically characterized by alpha-synuclein inclusions. Increasing evidence supports the aggregation of alpha-synuclein in specific brain areas early in the disease course, followed by the spreading of alpha-synuclein pathology to multiple brain regions. However, little is known about how the structure of alpha-synuclein fibrils influence its ability to seed endogenous alpha-synuclein in recipient cells. Here, we aggregated alpha-synuclein by seeding with homogenates of PD- and MSA-confirmed brain tissue, determined the resulting alpha-synuclein fibril structures by cryo-electron microscopy, and characterized their seeding potential in mouse primary oligodendroglial cultures. The combined analysis shows that the two patient material-amplified alpha-synuclein fibrils share a similar protofilament fold but differ in their inter-protofilament interface and their ability to recruit endogenous alpha-synuclein. Our study indicates that the quaternary structure of alpha-synuclein fibrils modulates the seeding of alpha-synuclein pathology inside recipient cells. It thus provides an important advance in the quest to understand the connection between the structure of alpha-synuclein fibrils, cellular seeding/spreading, and ultimately the clinical manifestations of different synucleinopathies. Quaternary structure of alpha-synuclein fibrils characterized from human patients with Parkinson's disease and Multiple System Atrophy modulates seeding in mouse primary oligodendroglial cultures.