Fibrillation of α-synuclein triggered by bacterial endotoxin and lipid vesicles is modulated by N-terminal acetylation and familial Parkinson's disease mutations.

Autor: Monteiro Neto JR; Laboratory of Biological Chemistry of Neurodegenerative Disorders, Institute of Chemistry, Federal University of Rio de Janeiro, Brazil., Lima VA; Laboratory of Biological Chemistry of Neurodegenerative Disorders, Institute of Chemistry, Federal University of Rio de Janeiro, Brazil., Follmer C; Laboratory of Biological Chemistry of Neurodegenerative Disorders, Institute of Chemistry, Federal University of Rio de Janeiro, Brazil.
Jazyk: angličtina
Zdroj: The FEBS journal [FEBS J] 2024 Mar; Vol. 291 (6), pp. 1151-1167. Date of Electronic Publication: 2023 Dec 19.
DOI: 10.1111/febs.17027
Abstrakt: It has been hypothesized that --Parkinson's disease (PD) may be initiated in the gastrointestinal tract, before manifesting in the central nervous system. In this respect, it was demonstrated that lipopolysaccharide (LPS), an endotoxin from gram-negative bacteria, accelerates the in vitro formation of α-synuclein (aSyn) fibrils, whose intracellular deposits is a histological hallmark of the degeneration of dopaminergic neurons in PD. Herein, N-terminal acetylation and missense mutations of aSyn (A30P, A53T, E46K, H50Q and G51D) linked to rare, early-onset forms of familial PD were investigated regarding their effect on aSyn aggregation stimulated by either LPS or small unilamellar lipid vesicles (SUVs). Our findings indicated that LPS as well as SUVs induce the fibrillation of N-terminally acetylated wild-type aSyn (Ac-aSyn-WT) more remarkably than the non-acetylated protein, while the LPS-free protein alone did not undergo fibrillation under our assay conditions. In addition, with the exception of A30P, PD mutations increased the fibrillation of Ac-aSyn in the presence of LPS compared with Ac-aSyn-WT. The most pronounced effect of LPS was noticed for A53T, as observed when either Thioflavin-T or JC-1 were used as fluorescent probes for fibrils. Overall, our results suggest for the first time the existence of a synergy between LPS and PD mutations/N-terminal acetylation toward aSyn fibrillation.
(© 2023 Federation of European Biochemical Societies.)
Databáze: MEDLINE
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