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Structural Features and Toxicity of α-Synuclein Oligomers Grown in the Presence of DOPAC
The interplay between α-synuclein and dopamine derivatives is associated with oxidative stress-dependent neurodegeneration in Parkinson’s disease (PD). The formation in the dopaminergic neurons of intraneuronal inclusions containing aggregates of α-synuclein is a typical hallmark of PD. Even though...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199589/ https://www.ncbi.nlm.nih.gov/pubmed/34199427 http://dx.doi.org/10.3390/ijms22116008 |
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author | Palazzi, Luana Fongaro, Benedetta Leri, Manuela Acquasaliente, Laura Stefani, Massimo Bucciantini, Monica Polverino de Laureto, Patrizia |
author_facet | Palazzi, Luana Fongaro, Benedetta Leri, Manuela Acquasaliente, Laura Stefani, Massimo Bucciantini, Monica Polverino de Laureto, Patrizia |
author_sort | Palazzi, Luana |
collection | PubMed |
description | The interplay between α-synuclein and dopamine derivatives is associated with oxidative stress-dependent neurodegeneration in Parkinson’s disease (PD). The formation in the dopaminergic neurons of intraneuronal inclusions containing aggregates of α-synuclein is a typical hallmark of PD. Even though the biochemical events underlying the aberrant aggregation of α-synuclein are not completely understood, strong evidence correlates this process with the levels of dopamine metabolites. In vitro, 3,4-dihydroxyphenylacetaldehyde (DOPAL) and the other two metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylethanol (DOPET), share the property to inhibit the growth of mature amyloid fibrils of α-synuclein. Although this effect occurs with the formation of differently toxic products, the molecular basis of this inhibition is still unclear. Here, we provide information on the effect of DOPAC on the aggregation properties of α-synuclein and its ability to interact with membranes. DOPAC inhibits α-synuclein aggregation, stabilizing monomer and inducing the formation of dimers and trimers. DOPAC-induced oligomers did not undergo conformational transition in the presence of membranes, and penetrated the cell, where they triggered autophagic processes. Cellular assays showed that DOPAC reduced cytotoxicity and ROS production induced by α-synuclein aggregates. Our findings show that the early radicals resulting from DOPAC autoxidation produced covalent modifications of the protein, which were not by themselves a primary cause of either fibrillation or membrane binding inhibition. These findings are discussed in the light of the potential mechanism of DOPAC protection against the toxicity of α-synuclein aggregates to better understand protein and catecholamine biology and to eventually suggest a scaffold that can help in the design of candidate molecules able to interfere in α-synuclein aggregation. |
format | Online Article Text |
id | pubmed-8199589 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-81995892021-06-14 Structural Features and Toxicity of α-Synuclein Oligomers Grown in the Presence of DOPAC Palazzi, Luana Fongaro, Benedetta Leri, Manuela Acquasaliente, Laura Stefani, Massimo Bucciantini, Monica Polverino de Laureto, Patrizia Int J Mol Sci Article The interplay between α-synuclein and dopamine derivatives is associated with oxidative stress-dependent neurodegeneration in Parkinson’s disease (PD). The formation in the dopaminergic neurons of intraneuronal inclusions containing aggregates of α-synuclein is a typical hallmark of PD. Even though the biochemical events underlying the aberrant aggregation of α-synuclein are not completely understood, strong evidence correlates this process with the levels of dopamine metabolites. In vitro, 3,4-dihydroxyphenylacetaldehyde (DOPAL) and the other two metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylethanol (DOPET), share the property to inhibit the growth of mature amyloid fibrils of α-synuclein. Although this effect occurs with the formation of differently toxic products, the molecular basis of this inhibition is still unclear. Here, we provide information on the effect of DOPAC on the aggregation properties of α-synuclein and its ability to interact with membranes. DOPAC inhibits α-synuclein aggregation, stabilizing monomer and inducing the formation of dimers and trimers. DOPAC-induced oligomers did not undergo conformational transition in the presence of membranes, and penetrated the cell, where they triggered autophagic processes. Cellular assays showed that DOPAC reduced cytotoxicity and ROS production induced by α-synuclein aggregates. Our findings show that the early radicals resulting from DOPAC autoxidation produced covalent modifications of the protein, which were not by themselves a primary cause of either fibrillation or membrane binding inhibition. These findings are discussed in the light of the potential mechanism of DOPAC protection against the toxicity of α-synuclein aggregates to better understand protein and catecholamine biology and to eventually suggest a scaffold that can help in the design of candidate molecules able to interfere in α-synuclein aggregation. MDPI 2021-06-02 /pmc/articles/PMC8199589/ /pubmed/34199427 http://dx.doi.org/10.3390/ijms22116008 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Palazzi, Luana Fongaro, Benedetta Leri, Manuela Acquasaliente, Laura Stefani, Massimo Bucciantini, Monica Polverino de Laureto, Patrizia Structural Features and Toxicity of α-Synuclein Oligomers Grown in the Presence of DOPAC |
title | Structural Features and Toxicity of α-Synuclein Oligomers Grown in the Presence of DOPAC |
title_full | Structural Features and Toxicity of α-Synuclein Oligomers Grown in the Presence of DOPAC |
title_fullStr | Structural Features and Toxicity of α-Synuclein Oligomers Grown in the Presence of DOPAC |
title_full_unstemmed | Structural Features and Toxicity of α-Synuclein Oligomers Grown in the Presence of DOPAC |
title_short | Structural Features and Toxicity of α-Synuclein Oligomers Grown in the Presence of DOPAC |
title_sort | structural features and toxicity of α-synuclein oligomers grown in the presence of dopac |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199589/ https://www.ncbi.nlm.nih.gov/pubmed/34199427 http://dx.doi.org/10.3390/ijms22116008 |
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