4.7 Article

A Downsized and Optimised Intracellular Library-Derived Peptide Prevents Alpha-Synuclein Primary Nucleation and Toxicity Without Impacting Upon Lipid Binding

期刊

JOURNAL OF MOLECULAR BIOLOGY
卷 433, 期 24, 页码 -

出版社

ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2021.167323

关键词

peptide; amyloid aggregation; primary nucleation; lipid vesicles; Parkinson's disease

资金

  1. BRACE [BR16/064]
  2. Alzheimer's Research UK [ARUK-PG2018-003]
  3. Biotechnology and Biological Sciences Research Council [BB/T018275/1]
  4. BBSRC [BB/T018275/1] Funding Source: UKRI

向作者/读者索取更多资源

A peptide inhibitor was derived from a cell library screen to block aggregation of alpha-synuclein (α S) and its conversion into toxic species. Truncation and alanine scan analysis were used to determine inhibitory residues and improve peptide efficacy without disrupting α S lipid-binding. This work aims to develop a potent peptide antagonist of α S pathogenicity while preserving its native function.
Misfolding and aggregation of alpha-synuclein (alpha S) within dopaminergic neurons is a key factor in the development and progression of a group of age-related neurodegenerative diseases, termed synucleinopathies, that include Parkinson's disease (PD). We previously derived a peptide inhibitor from a 209,952-member intracellular library screen by employing the preNAC region (45-54) as a design template. At least six single-point mutations firmly linked to early-onset Parkinson's disease (E46K, H50Q, G51D, A53T/E/V) are located within this region, strongly implicating a pathogenic role within aS that leads to increased cytotoxicity. A library-derived ten residue peptide, 4554W, was consequently shown to block alpha S aggregation at the point of primary nucleation via lipid induction, inhibiting its conversion into downstream cytotoxic species. Here we couple truncation with a full alanine scan analysis, to establish the effect upon the alpha S aggregation pathway relative to 4554W. This revealed the precise residues responsible for eliciting inhibitory interaction and function, as well as those potentially amenable to modification or functionalisation. We find that modification N6A combined with N-terminal truncation results in a peptide of significantly increased efficacy. Importantly, our data demonstrate that the peptide does not directly disrupt alpha S lipid-binding, a desirable trait since antagonists of alpha S aggregation and toxicity should not impede association with small synaptic neurotransmitter vesicles, and thus not disrupt dopaminergic vesicle fusion and recycling. This work paves the way toward the major aim of deriving a highly potent peptide antagonist of alpha S pathogenicity without impacting on native aS function. (C) 2021 Elsevier Ltd. All rights reserved.

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