Small-angle neutron scattering reveals the assembly of alpha-synuclein in lipid membranes

Biochimica Et Biophysica Acta
Divina AnunciadoHugh O'Neill

Abstract

The aggregation of α-synuclein (asyn), an intrinsically disordered protein (IDP), is a hallmark in Parkinson's disease (PD). We investigated the conformational changes that asyn undergoes in the presence of membrane and membrane mimetics using small-angle neutron scattering (SANS). In solution, asyn is monomeric and unfolded assuming an ensemble of conformers spanning extended and compact conformations. Using the contrast variation technique and SANS, the protein scattering signal in the membrane-protein complexes is selectively highlighted in order to monitor its conformational changes in this environment. We showed that in the presence of phospholipid membranes asyn transitions from a monodisperse state to aggregated structures with sizes ranging from 200 to 900Å coexisting with the monomeric species. Detailed SANS data analysis revealed that asyn aggregates have a hierarchical organization in which clusters of smaller asyn aggregates assemble to form the larger structures. This study provides new insight into the mechanism of asyn aggregation. We propose an aggregation mechanism in which stable asyn aggregates seed the aggregation process and hence the hierarchical assembly of structures. Our findings demonstrate that membra...Continue Reading

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Citations

Oct 13, 2016·Journal of the American Society for Mass Spectrometry·Antonino NatalelloRita Grandori
Jan 11, 2019·International Journal of Analytical Chemistry·Keishi SugaHiroshi Umakoshi
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Dec 11, 2020·Langmuir : the ACS Journal of Surfaces and Colloids·Shuo QianLuke A Clifton
Jul 15, 2020·The Journal of Physical Chemistry Letters·Kevin PounotTilo Seydel

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