Structure based aggregation studies reveal the presence of helix-rich intermediate during α-Synuclein aggregation

Scientific Reports
Dhiman GhoshSamir K Maji

Abstract

Mechanistic understanding of nucleation dependent polymerization by α-synuclein (α-Syn) into toxic oligomers and amyloids is important for the drug development against Parkinson's disease. However the structural and morphological characterization during nucleation and subsequent fibrillation process of α-Syn is not clearly understood. Using a variety of complementary biophysical techniques monitoring entire pathway of nine different synucleins, we found that transition of unstructured conformation into β-sheet rich fibril formation involves helix-rich intermediates. These intermediates are common for all aggregating synucleins, contain high solvent-exposed hydrophobic surfaces, are cytotoxic to SHSY-5Y cells and accelerate α-Syn aggregation efficiently. A multidimensional NMR study characterizing the intermediate accompanied with site-specific fluorescence study suggests that the N-terminal and central portions mainly participate in the helix-rich intermediate formation while the C-terminus remained in an extended conformation. However, significant conformational transitions occur at the middle and at the C-terminus during helix to β-sheet transition as evident from Trp fluorescence study. Since partial helix-rich intermediates...Continue Reading

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Methods Mentioned

BETA
NMR
AFM
electron microscopy
protein folding
flow cytometry
fluorescence assay
fluorescence spectroscopy

Software Mentioned

opus
CONTINLL
BDFACS Diva
Sparky
SELCON3
65
ClustalW
CDPro
Topspin
CDSSTR

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