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- W4211142435 abstract "Abstract α-Synuclein inclusions are a pathological hallmark of several neurodegenerative diseases. Although it has been demonstrated a relationship between fibril polymorphism and different pathologies, the molecular origins of polymorphism are not understood. Employing biophysical approaches, we revealed that the conformational state of the monomeric αSyn is responsible for fibril polymorphism: αSyn adopts specific conformations at high NaCl that produce rod fibrils, and different conformations at low NaCl that generate twisted fibrils. Using NMR, we found that the high NaCl conformations establish a polar interaction between the initial part of the NAC region and a wide section of the C-terminus domain. These high NaCl conformations can be commonly promoted by changes in the chemical environment, like NaCl, the presence of Ca 2+ or cellular components, like endotoxins, that alter the interaction NAC/C-terminus domain. Our results provide mechanistic insights that explain how the behavior of the C-terminus domain imparts polymorphism during the fibril formation. Significance Statement The accumulation of the protein α-Synuclein into amyloid aggregates in the brain is a key characteristic of neurodegenerative disorders like Parkinson’s disease and multiple system atrophy. Intensive research has demonstrated that structurally different amyloid fibrils are related to the development of different diseases; however, the molecular mechanisms that originate such fibril diversity from the same protein remain unknown. In this work, we discovered that the conformational state of the monomeric αSyn, regulated by an intramolecular polar interaction NAC region/C-terminus domain, is crucial for the generation of different fibrils. Our results represent the monomeric molecular events behind the diversity of fibrils and open the conformational state of αSyn as a target to understand how the fibrils get formed in the brain." @default.
- W4211142435 created "2022-02-13" @default.
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- W4211142435 date "2022-02-10" @default.
- W4211142435 modified "2023-09-30" @default.
- W4211142435 title "Conformational change in the monomeric alpha-synuclein imparts fibril polymorphs" @default.
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- W4211142435 doi "https://doi.org/10.1101/2022.02.10.479831" @default.
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