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Structure based aggregation studies reveal the presence of helix-rich intermediate during α-Synuclein aggregation
Open accessAbstract
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 were also observed for other amyloidogenic proteins such as Aβ and IAPP, we hypothesize that this class of intermediates may be one of the important intermediates for amyloid formation pathway by many natively unstructured protein/peptides and represent a potential target for drug development against amyloid diseases.
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α‐Synuclein aggregation nucleates through liquid‐liquid phase separation
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Self-citationα-Synuclein misfolding and aggregation: Implications in Parkinson’s disease pathogenesis
Mehra, S., Sahay, S., & Maji, S. K. (2019) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2019.03.001 · Cited by 499
Self-citationDetection of amyloid fibrils in Parkinson’s disease using plasmonic chirality
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The Role of α-Synuclein Oligomers in Parkinson’s Disease
Du, X.-Y., Xie, X.-X., & Liu, R.-T. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21228645 · Cited by 234
Roeters, S. J., Iyer, A., Pletikapić, G., Kogan, V., Subramaniam, V., & Woutersen, S. (2017) · Scientific Reports · doi:10.1038/srep41051 · Cited by 146
Metadata
- Authors
- Ghosh, D., Singh, P. K., Sahay, S., Jha, N. N., Jacob, R. S., Sen, S., Kumar, A., Riek, R., & Maji, S. K.
- Venue
- Scientific Reports
- Published
- 2015-03-18
- Volume
- 5
- Issue
- 1
- Pages
- 9228-9228
- ISSN
- 2045-2322 (ISSN-L)
- OpenAlex
- W2032487213
- Cited by
- 211
- References
- 12
- FWCI
- 10.53
- Type
- journal article
- Language
- en
- Open access
- gold
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