2026-04-29T20:47:15Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/230322024-11-28T20:15:49Zcom_20.500.12105_15322com_20.500.12105_2051col_20.500.12105_16967
Repisalud
author
Marino, Laura
author
Ramis, Rafael
author
Casasnovas, Rodrigo
author
Ortega-Castro, Joaquin
author
Vilanova, Bartolome
author
Frau, Juan
author
Adrover, Miquel
2024-09-13T09:15:56Z
2024-09-13T09:15:56Z
2020-03-28
Marino L, Ramis R, Casasnovas R, Ortega-Castro J, Vilanova B, Frau J, et al. Unravelling the effect of N(epsilon)-(carboxyethyl)lysine on the conformation, dynamics and aggregation propensity of alpha-synuclein. Chem Sci. 2020 Mar 28;11(12):3332-44.
10.1039/d0sc00906g
2041-6539
2041-6520
Chemical Science
http://hdl.handle.net/20.500.13003/17249
34122841
2-s2.0-85082721975
https://hdl.handle.net/20.500.12105/23032
528663000022
alpha-Synuclein (alpha S) 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. alpha S 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 alpha S, 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 alpha S 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 alpha S 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.
eng
Unravelling the effect of N(epsilon)-(carboxyethyl)lysine on the conformation, dynamics and aggregation propensity of alpha-synuclein
research article