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

Azad Farzadfard, Jannik Nedergaard Pedersen, Georg Meisl, Arun Kumar Somavarapu, Parvez Alam, Louise Goksøyr, Morten Agertoug Nielsen, Adam Frederik Sander, Tuomas P J Knowles, Jan Skov Pedersen, Daniel Erik Otzen*

*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Abstract

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.

Original languageEnglish
Article number123
JournalCommunications Biology
Volume5
Issue1
Number of pages10
DOIs
Publication statusPublished - Feb 2022

Keywords

  • DISRUPTION
  • FIBRIL
  • INFLUX
  • MECHANISM
  • NMR
  • TOXICITY
  • TRUNCATION
  • X-RAY-SCATTERING

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