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Issue 12, 2020
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Unravelling the effect of N(ε)-(carboxyethyl)lysine on the conformation, dynamics and aggregation propensity of α-synuclein

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Abstract

α-Synuclein (αS) aggregation is a hallmark in several neurodegenerative diseases. Among them, Parkinson's disease is highlighted, characterized by the intraneuronal deposition of Lewy bodies (LBs) which causes the loss of dopaminergic neurons. αS is the main component of LBs and in them, it usually contains post-translational modifications. One of them is the formation of advanced glycation end-products (mainly CEL and MOLD) arising from its reaction with methylglyoxal. Despite its biological relevance, there are no data available proving the effect of glycation on the conformation of αS, nor on its aggregation mechanism. This has been hampered by the formation of a heterogeneous set of compounds that precluded conformational studies. To overcome this issue, we have here produced αS homogeneously glycated with CEL. Its use, together with different biophysical techniques and molecular dynamics simulations, allowed us to study for the first time the effect of glycation on the conformation of a protein. CEL extended the conformation of the N-terminal domain as a result of the loss of transient N-/C-terminal long-range contacts while increasing the heterogeneity of the conformational population. CEL also inhibited the αS aggregation, but it was not able to disassemble preexisting amyloid fibrils, thus proving that CEL found on LBs must be formed in a later event after aggregation.

Graphical abstract: Unravelling the effect of N(ε)-(carboxyethyl)lysine on the conformation, dynamics and aggregation propensity of α-synuclein

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Supplementary files

Article information


Submitted
16 Feb 2020
Accepted
27 Feb 2020
First published
10 Mar 2020

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2020,11, 3332-3344
Article type
Edge Article

Unravelling the effect of N(ε)-(carboxyethyl)lysine on the conformation, dynamics and aggregation propensity of α-synuclein

L. Mariño, R. Ramis, R. Casasnovas, J. Ortega-Castro, B. Vilanova, J. Frau and M. Adrover, Chem. Sci., 2020, 11, 3332
DOI: 10.1039/D0SC00906G

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