Structural heterogeneity of α-synuclein fibrils amplified from patient brain extracts

STROHÄKER, TIMO; JUNG, BYUNG CHUL; LIOU, SHU-HAO; FERNANDEZ, CLAUDIO O.; RIEDEL, DIETMAR; BECKER, STEFAN; HALLIDAY, GLENDA M.; BENNATI, MARINA; KIM, WOOJIN S.; LEE, SEUNG-JAE; ZWECKSTETTER, MARKUS

NATURE COMMUNICATIONS

Nature

Año: 2019 vol. 10

2041-1723

Parkinson?s disease (PD) and Multiple System Atrophy (MSA) are clinically distinctive dis-eases that feature a common neuropathological hallmark of aggregated α-synuclein. Little isknown about how differences in α-synuclein aggregate structure affect disease phenotype.Here, we amplified α-synuclein aggregates from PD and MSA brain extracts and analyzed theconformational properties using fluorescent probes, NMR spectroscopy and electron para-magnetic resonance. We also generated and analyzed several in vitro α-synuclein poly-morphs. We found that brain-derived α-synuclein fibrils were structurally different to all ofthe in vitro polymorphs analyzed. Importantly, there was a greater structural heterogeneityamong α-synuclein fibrils from the PD brain compared to those from the MSA brain, possiblyreflecting on the greater variability of disease phenotypes evident in PD. Our findings havesignificant ramifications for the use of non-brain-derived α-synuclein fibrils in PD and MSAstudies, and raise important questions regarding the one disease-one strain hypothesis in thestudy of α-synucleinopathies.