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...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-06-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/11/6008 |
| _version_ | 1797531651709861888 |
|---|---|
| author | Luana Palazzi Benedetta Fongaro Manuela Leri Laura Acquasaliente Massimo Stefani Monica Bucciantini Patrizia Polverino de Laureto |
| author_facet | Luana Palazzi Benedetta Fongaro Manuela Leri Laura Acquasaliente Massimo Stefani Monica Bucciantini Patrizia Polverino de Laureto |
| author_sort | Luana Palazzi |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T10:46:45Z |
| format | Article |
| id | doaj.art-580295d8d3ec4f0eb5ca5f0431bfb25d |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T10:46:45Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-580295d8d3ec4f0eb5ca5f0431bfb25d2023-11-21T22:31:02ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-06-012211600810.3390/ijms22116008Structural Features and Toxicity of α-Synuclein Oligomers Grown in the Presence of DOPACLuana Palazzi0Benedetta Fongaro1Manuela Leri2Laura Acquasaliente3Massimo Stefani4Monica Bucciantini5Patrizia Polverino de Laureto6Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, ItalyDepartment of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, ItalyDepartment of Biomedical, Experimental and Clinical Sciences, University of Firenze, 50134 Firenze, ItalyDepartment of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, ItalyDepartment of Biomedical, Experimental and Clinical Sciences, University of Firenze, 50134 Firenze, ItalyDepartment of Biomedical, Experimental and Clinical Sciences, University of Firenze, 50134 Firenze, ItalyDepartment of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, ItalyThe 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.https://www.mdpi.com/1422-0067/22/11/6008α-synuclein aggregation inhibitionfibril inhibitionDOPACParkinson’s diseaseprotein oligomerizationoligomer toxicity |
| spellingShingle | Luana Palazzi Benedetta Fongaro Manuela Leri Laura Acquasaliente Massimo Stefani Monica Bucciantini Patrizia Polverino de Laureto Structural Features and Toxicity of α-Synuclein Oligomers Grown in the Presence of DOPAC International Journal of Molecular Sciences α-synuclein aggregation inhibition fibril inhibition DOPAC Parkinson’s disease protein oligomerization oligomer toxicity |
| 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 | α-synuclein aggregation inhibition fibril inhibition DOPAC Parkinson’s disease protein oligomerization oligomer toxicity |
| url | https://www.mdpi.com/1422-0067/22/11/6008 |
| work_keys_str_mv | AT luanapalazzi structuralfeaturesandtoxicityofasynucleinoligomersgrowninthepresenceofdopac AT benedettafongaro structuralfeaturesandtoxicityofasynucleinoligomersgrowninthepresenceofdopac AT manuelaleri structuralfeaturesandtoxicityofasynucleinoligomersgrowninthepresenceofdopac AT lauraacquasaliente structuralfeaturesandtoxicityofasynucleinoligomersgrowninthepresenceofdopac AT massimostefani structuralfeaturesandtoxicityofasynucleinoligomersgrowninthepresenceofdopac AT monicabucciantini structuralfeaturesandtoxicityofasynucleinoligomersgrowninthepresenceofdopac AT patriziapolverinodelaureto structuralfeaturesandtoxicityofasynucleinoligomersgrowninthepresenceofdopac |