α-Synuclein polymorphism determines oligodendroglial dysfunction

Synucleinopathies, such as Parkinson's disease (PD) and Multiple System Atrophy (MSA) are progressive and unremitting neurological diseases. For both PD and MSA, alpha-synuclein fibril inclusions inside brain cells are neuropathological hallmarks. In addition, amplification of alpha-synuclein fibrils from body fluids is a potential biomarker distinguishing PD from MSA. However, little is known about the structure of alpha-synuclein fibrils amplified from human samples and its connection to alpha-synuclein fibril structure in the human brain. Here we amplified alpha-synuclein fibrils from PD and MSA brain tissue, characterized its seeding potential in oligodendroglia, and determined the 3D structures by cryo-electron microscopy. We show that the alpha-synuclein fibrils from a MSA patient are more potent in recruiting the endogenous alpha-synuclein and evoking a redistribution of TPPP/p25alpha protein in mouse primary oligodendroglial cultures compared to those amplified from a PD patient. Cryo-electron microscopy shows that the PD- and MSA-amplified alpha-synuclein fibrils share a similar protofilament fold but differ in their inter-protofilament interface. The structures of the brain-tissue amplified alpha-synuclein fibrils are also similar to other in vitro and ex vivo alpha-synuclein fibrils. Together with published data, our results suggest that aSyn fibrils differ between PD and MSA in their quaternary arrangement and could further vary between different forms of PD and MSA.