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The C-terminal tail of α-synuclein protects against aggregate replication but is critical for oligomerization.

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Farzadfard, Azad 
Pedersen, Jannik Nedergaard 
Somavarapu, Arun Kumar 
Alam, Parvez 


Aggregation of the 140-residue protein α-synuclein (αSN) is a key factor in the etiology of Parkinson's disease. Although the intensely anionic C-terminal domain (CTD) of αSN does not form part of the amyloid core region or affect membrane binding ability, truncation or reduction of charges in the CTD promotes fibrillation through as yet unknown mechanisms. Here, we study stepwise truncated CTDs and identify a threshold region around residue 121; constructs shorter than this dramatically increase their fibrillation tendency. Remarkably, these effects persist even when as little as 10% of the truncated variant is mixed with the full-length protein. Increased fibrillation can be explained by a substantial increase in self-replication, most likely via fragmentation. Paradoxically, truncation also suppresses toxic oligomer formation, and oligomers that can be formed by chemical modification show reduced membrane affinity and cytotoxicity. These remarkable changes correlate to the loss of negative electrostatic potential in the CTD and highlight a double-edged electrostatic safety guard.



Article, /631/57, /631/337, /82/16, /82/29, /82/80, /82/83, /101/28, article

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Commun Biol

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Springer Science and Business Media LLC