Abstract
Misfolding and aggregation of alpha-synuclein (αS) into toxic conformations is involved in numerous neurodegenerative diseases. In Parkinson's disease (PD), this occurs within dopaminergic neurons, causing cell death and disease symptoms. During αS aggregation, many protein-protein interactions (PPIs) form over broad and flat protein surfaces, limiting potential for small-molecule intervention. Peptides, however, harbor great therapeutic promise since they can selectively engage with and modulate the large surface areas involved yet are small enough to function as druggable agents if suitably structured. Here, we explore the first 25 residues of αS (αS 1–25) as a template for peptide-based αS aggregation antagonists. We report that αS 1–25 inhibits lipid-induced αS aggregation in a dose-dependent manner. αS 1–25 functions by binding to lipids to prevent αS binding, with both αS and peptide requiring lipid for inhibition to occur. These findings present a potential mechanistic route for the treatment or prevention of PD.
Original language | English |
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Article number | 101563 |
Journal | Cell Reports Physical Science |
Volume | 4 |
Issue number | 9 |
Early online date | 24 Aug 2023 |
DOIs | |
Publication status | Published - 20 Sept 2023 |
Funding
R.M.M. would like to thank Philip Fletcher, Diana Lednitzky, and Silvia Martinez Micol for their assistance with the transmission electron microscope. R.M.M. thanks BRACE for award of a PhD studentship (BR16/064). S.G.A. J.M.M. and M.P.C. thank the BBSRC SWBio Doctoral Training Program studentship (BB/T008741/1). J.M.M. and R.M.M. also thank Alzheimer's Research UK (ARUK-PG2018-003). M.P.C. is thankful for EPSRC EP/L016354/1. We also thank BBSRC/EPSRC for funding C.W. and the Bristol 700 MHz NMR facility through the Bristol Centre for Synthetic Biology (BB/L01386X/1). R.M.M. S.G.A. and C.W. conducted the experiments and contributed to the experimental design. J.M.M. and M.P.C. directed the research and experimental design. All authors participated in data analysis and writing of the paper. The authors declare no competing interests.
Keywords
- Parkinson's disease
- alpha-synuclein
- amyloid
- lipids
- peptide
- protein aggregation
ASJC Scopus subject areas
- General Engineering
- General Energy
- General Physics and Astronomy
- General Chemistry
- General Materials Science