Dynamic Properties of Human α-Synuclein Related to Propensity to Amyloid Fibril Formation.

Dynamic Properties of Human α-Synuclein Related to Propensity to Amyloid Fibril Formation.

Publication date: Jun 07, 2019

α-synuclein (αSyn) is an intrinsically disordered protein (IDP) that can form amyloid fibrils. Fibrils of αSyn are implicated with the pathogenesis of Parkinson’s disease and other synucleinopathies. Elucidating the mechanism of fibril formation of αSyn is therefore important for understanding the mechanism of the pathogenesis of these diseases. Fibril formation of αSyn is sensitive to solution conditions, suggesting that fibril formation of αSyn arises from the changes in its inherent physico-chemical properties, particularly its dynamic properties because IDPs such as αSyn utilize their inherent flexibility to function. Characterizing these properties under various conditions should provide insights into the mechanism of fibril formation. Here, using the quasielastic neutron scattering (QENS) and small-angle X-ray scattering (SAXS) techniques, we investigated the dynamic and structural properties of αSyn under the conditions, where mature fibrils are formed (pH 7.4 with a high salt concentration), where clumping of short fibrils occurs (pH 4.0), and where fibril formation is not completed (pH 7.4). The SAXS measurements showed that the extended structures at pH 7.4 with a high salt concentration become compact at pH 4.0 and 7.4. The QENS measurements showed that both intra-molecular segmental motions and local motions such as side-chain motions are enhanced at pH 7.4 with a high salt concentration, compared to those at pH 7.4 without salt, whereas only the local motions are enhanced at pH 4.0. These results imply that fibril formation of αSyn requires not only the enhanced local motions but also the segmental motions such that proper inter-molecular interactions are possible.

Concepts Keywords
Amyloid Amyloid
Compact Fibers
Fibril Structural proteins
Fibrils Histopathology
IDPs Fibril
Parkinson
Pathogenesis
Salt
SAXS
Scattering
Side Chain
X Ray

Semantics

Type Source Name
gene UNIPROT TNFSF14
gene UNIPROT P4HTM
gene UNIPROT RAB35
gene UNIPROT SH3YL1
disease DOID synucleinopathies
gene UNIPROT IDH1
gene UNIPROT IDH2
gene UNIPROT SYNM
gene UNIPROT FYN

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