Conformational change of a-synuclein fibrils in cerebrospinal fluid from different clinical phases of Parkinson's disease

a-Synuclein (a-syn) has been shown to form various conformational fibrils associated with different synuclei-nopathies. But whether the conformation of a-syn fibrils changes during disease progression is unclear. Here, we amplified a-syn aggregates from the cerebrospinal fluid (CSF) of patients with Parkinson's disease (PD) staged in preclinical PD (pre-PD), middle-to late-stage PD (mid-PD), and late-stage PD (late-PD). Our results show that a-syn fibrils derived from the late-PD patient are most potent in inducing endogenous a-syn aggregation in primary neurons, followed by the mid-PD and pre-PD fibrils. By using cryo-electron mi-croscopy, we further determined the high-resolution structures of the CSF-amplified fibrils. The structures exhibit remarkable differences in a minor but significant population of conformational species in different staged samples. Our work demonstrates structural and pathological differences between a-syn fibrils derived from PD patients at a spectrum of clinical stages, which suggests potential conformational transition of a-syn fibrils during the progression of PD.