Modulation of Alpha-Synuclein Aggregation by Dopamine Analogs

Herrera, Fernando
Bek, Alpan
Losasso, Valeria
Candotti, Michela
Benetti, Federico
Carlino, Elvio
Kranjc, Agata
Lazzarino, Marco
Gustincich, Stefano
Carloni, Paolo
Legname, Giuseppe
The action of dopamine on the aggregation of the unstructured alpha-synuclein (alpha-syn) protein may be linked to the pathogenesis of Parkinson's disease. Dopamine and its oxidation derivatives may inhibit alpha-syn aggregation by non-covalent binding. Exploiting this fact, we applied an integrated computational and experimental approach to find alternative ligands that might modulate the fibrillization of alpha-syn. Ligands structurally and electrostatically similar to dopamine were screened from an established library. Five analogs were selected for in vitro experimentation from the similarity ranked list of analogs. Molecular dynamics simulations showed they were, like dopamine, binding non-covalently to alpha-syn and, although much weaker than dopamine, they shared some of its binding properties. In vitro fibrillization assays were performed on these five dopamine analogs. Consistent with our predictions, analyses by atomic force and transmission electron microscopy revealed that all of the selected ligands affected the aggregation process, albeit to a varying and lesser extent than dopamine, used as the control ligand. The in silico/in vitro approach presented here emerges as a possible strategy for identifying ligands interfering with such a complex process as the fibrillization of an unstructured protein.


Identification of a contact region between the tridecapeptide alpha-factor mating pheromone of Saccharomyces cerevisiae and its G protein-coupled receptor by photoaffinity labeling.
Henry, Lk; Khare, S; Son, Çağdaş Devrim; Babu, Vv; Naider, F; Becker, Jm (2002-05-14)
Saccharomyces cerevisiae haploid cells communicate with their opposite mating type through peptide pheromones (alpha-factor and a-factor) that activate G protein-coupled receptors (GPCRs). S. cerevisiae was used as a model system for the study of peptide-responsive GPCRs. Here, we detail the synthesis and characterization of a number of a-factor (Trp-His-Trp-Leu-Gln-Leu-Lys-Pro-Gly-Gln-Pro-Met-Tyr) pheromone analogues containing the photo-cross-linkable group 4-benzoyl-L-phenylalanine (Bpa). Following chara...
Synthesis of dopamine functionalized silver nanoparticles together with possible interactions between silver and dopamine having different oxidation forms
Kanbertay, Elif; Volkan, Mürvet; Department of Chemistry (2013)
Dopamine is a neurotransmitter found in central nerve system which has a vital role for human health. Dopamine oxidation in body is an important issue since it may form reactive metabolites which can be toxic to the cell. Surface-enhanced Raman scattering (SERS) is currently recognized as one of the most sensitive spectroscopic tools, which can be exploited for ultrasensitive chemical and biological detection, addition to providing structural information on the systems of interest. SERS of dopamine displays...
Impaired inhibitory GABAergic synaptic transmission and transcription studied in single neurons by Patch-seq in Huntington's disease
Paraskevopoulou, Foteini; Parvizi, Poorya; Senger, Gokce; Tunçbağ, Nurcan; Rosenmund, Christian; Yildirim, Ferah (2021-05-11)
Transcriptional dysregulation in Huntington's disease (HD) causes functional deficits in striatal neurons. Here, we performed Patchsequencing (Patch-seq) in an in vitro HD model to investigate the effects of mutant Huntingtin (Htt) on synaptic transmission and gene transcription in single striatal neurons. We found that expression of mutant Htt decreased the synaptic output of striatal neurons in a cell autonomous fashion and identified a number of genes whose dysregulation was correlated with physiological...
Prediction of the effects of single amino acid variations on protein functionality with structural and annotation centric modeling
Cankara, Fatma; Tunçbağ, Nurcan; Department of Bioinformatics (2020)
Whole-genome and exome sequencing studies have indicated that genomic variations may cause deleterious effects on protein functionality via various mechanisms. Single nucleotide variations that alter the protein sequence, and thus, the structure and the function, namely non-synonymous SNPs (nsSNP), are associated with many genetic diseases in human. The current rate of manually annotating the reported nsSNPs cannot catch up with the rate of producing new sequencing data. To aid this process, automated compu...
CXXC5 as an unmethylated CpG dinucleotide binding protein contributes to estrogen-mediated cellular proliferation.
Ayaz, G; Razizadeh, N; Yaşar, P; Kars, G; Kahraman, Deniz Cansen; Saatci, Ö; Şahin, Ö; Çetin-Atalay, R; Muyan, M (2020-04-06)
Evidence suggests that the CXXC type zinc finger (ZF-CXXC) protein 5 (CXXC5) is a critical regulator/integrator of various signaling pathways that include the estrogen (E2)-estrogen receptor α (ERα). Due to its ZF-CXXC domain, CXXC5 is considered to be a member of the ZF-CXXC family, which binds to unmethylated CpG dinucleotides of DNA and through enzymatic activities for DNA methylation and/or chromatin modifications generates a chromatin state critical for gene expressions. Structural/functional features ...
Citation Formats
D. LATAWİEC et al., “Modulation of Alpha-Synuclein Aggregation by Dopamine Analogs,” PLOS ONE, pp. 0–0, 2010, Accessed: 00, 2020. [Online]. Available: