[en] 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.
Palazzi, Luana ✱; Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy
Fongaro, Benedetta ✱; Université de Liège - ULiège > Département des sciences de la vie > Centre d'Ingénierie des Protéines (CIP) ; Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy
Leri, Manuela; Department of Biomedical, Experimental and Clinical Sciences, University of Firenze, 50134 Firenze, Italy
Acquasaliente, Laura ; Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy
Stefani, Massimo; Department of Biomedical, Experimental and Clinical Sciences, University of Firenze, 50134 Firenze, Italy
Bucciantini, Monica; Department of Biomedical, Experimental and Clinical Sciences, University of Firenze, 50134 Firenze, Italy
Polverino de Laureto, Patrizia ; Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy
✱ These authors have contributed equally to this work.
Language :
English
Title :
Structural Features and Toxicity of α-Synuclein Oligomers Grown in the Presence of DOPAC.
UNIPD - Università degli Studi di Padova [IT] MIUR - Ministero dell'Istruzione, dell'Università e della Ricerca [IT] UniFI - University of Florence [IT]
Funding text :
This research was supported by Progetti di Ateneo-University of Padova 2017-N. C93C1800002600, MIUR-PNRA to P.P. (Programma Nazionale Ricerche in Antartide) (grant number PNRA18_00147). M.L. was supported by ANCC-COOP/Airalzh ONLUS [Reg. n◦ 0043966.30-10-359 2014-u] through University of Florence [D.R.595/2016].Funding: This research was supported by Progetti di Ateneo-University of Padova 2017-N. C93C1800002600, MIUR-PNRA to P.P. (Programma Nazionale Ricerche in Antartide) (grant number PNRA18_00147). M.L. was supported by ANCC-COOP/Airalzh ONLUS [Reg. n◦ 0043966.30-10-359 2014-u] through University of Florence [D.R.595/2016].
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