PT  - JOURNAL ARTICLE
AU  - Benedikt Frieg
AU  - James A. Geraets
AU  - Timo Strohäker
AU  - Christian Dienemann
AU  - Panagiota Mavroeidi
AU  - Byung Chul Jung
AU  - Woojin S. Kim
AU  - Seung-Jae Lee
AU  - Maria Xilouri
AU  - Markus Zweckstetter
AU  - Gunnar F. Schröder
TI  - α-Synuclein polymorphism determines oligodendroglial dysfunction
AID  - 10.1101/2021.07.09.451731
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.07.09.451731
4099  - http://biorxiv.org/content/early/2021/07/10/2021.07.09.451731.short
4100  - http://biorxiv.org/content/early/2021/07/10/2021.07.09.451731.full
AB  - Synucleinopathies, such as Parkinson’s disease (PD) and Multiple System Atrophy (MSA) are progressive and unremitting neurological diseases. For both PD and MSA, α-synuclein fibril inclusions inside brain cells are neuropathological hallmarks. In addition, amplification of α-synuclein fibrils from body fluids is a potential biomarker distinguishing PD from MSA. However, little is known about the structure of α-synuclein fibrils amplified from human samples and its connection to α-synuclein fibril structure in the human brain. Here we amplified α-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 α-synuclein fibrils from a MSA patient are more potent in recruiting the endogenous α-synuclein and evoking a redistribution of TPPP/p25α protein in mouse primary oligoden-droglial cultures compared to those amplified from a PD patient. Cryo-electron microscopy shows that the PD- and MSA-amplified α-synuclein fibrils share a similar protofilament fold but differ in their inter-protofilament interface. The structures of the brain-tissue amplified α-synuclein fibrils are also similar to other in vitro and ex vivo α-synuclein fibrils. Together with published data, our results suggest that αSyn fibrils differ between PD and MSA in their quaternary arrangement and could further vary between different forms of PD and MSA.Competing Interest StatementS.-J.L. is a founder and co-CEO of Neuramedy Co., Ltd. The other authors declare no competing interests.