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

Abstract:

:Parkinson's disease (PD) and Multiple System Atrophy (MSA) are clinically distinctive diseases that feature a common neuropathological hallmark of aggregated α-synuclein. Little is known 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 the conformational properties using fluorescent probes, NMR spectroscopy and electron paramagnetic resonance. We also generated and analyzed several in vitro α-synuclein polymorphs. We found that brain-derived α-synuclein fibrils were structurally different to all of the in vitro polymorphs analyzed. Importantly, there was a greater structural heterogeneity among α-synuclein fibrils from the PD brain compared to those from the MSA brain, possibly reflecting on the greater variability of disease phenotypes evident in PD. Our findings have significant ramifications for the use of non-brain-derived α-synuclein fibrils in PD and MSA studies, and raise important questions regarding the one disease-one strain hypothesis in the study of α-synucleinopathies.

journal_name

Nat Commun

journal_title

Nature communications

authors

Strohäker T,Jung BC,Liou SH,Fernandez CO,Riedel D,Becker S,Halliday GM,Bennati M,Kim WS,Lee SJ,Zweckstetter M

doi

10.1038/s41467-019-13564-w

subject

Has Abstract

pub_date

2019-12-04 00:00:00

pages

5535

issue

1

issn

2041-1723

pii

10.1038/s41467-019-13564-w

journal_volume

10

pub_type

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