Modulation of Alpha-Synuclein Aggregation by Dopamine Analogs

Latawiec, Diane; Herrera, Fernando E.; Bek, Alpan; Losasso, Valeria; Candotti, Michela; Benetti, Federico; Carlino, Elvio; Kranjc, Agata; Lazzarino, Marco; Gustincich, Stefano; Carloni, Paolo; Legname, Giuseppe

doi:10.1371/journal.pone.0009234

Cited by 54 publications

(55 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with this finding, Herrera et al used molecular modeling and in vitro aggregation reactions to show that dopamine interacts non-covalently and nonspecifically through hydrophobic interactions with the YEMPS region to inhibit α-synuclein aggregation [180]. A subsequent study using molecular modeling supports the notion of non-covalent interactions between dopamine and α-synuclein [181], though the in vitro fibrillization experiments in this study did not assess this directly.…”

Section: Dopamine-modified α-Synuclein: Pathogen or Innocentmentioning

confidence: 55%

Targeting α-Synuclein as a Parkinson’s Disease Therapeutic

Esposito

2014

Topics in Medicinal Chemistry

View full text Add to dashboard Cite

α-Synuclein is a dynamic protein capable of assuming an ensemble of physiological and pathological structures. Its primary role in Parkinson's disease (PD) pathogenesis makes it an attractive though nonconventional therapeutic target. An understanding of α-synuclein intra-and intermolecular interactions and posttranslational modifications that lead to its misfolding, aggregation, accumulation, and cell-to-cell prion-like spreading is necessary to inform the design of α-synuclein-directed therapeutics. Native α-synuclein interacts with membranes and plays an important role in synaptic transmission and vesicle trafficking at the presynaptic terminal, though aggregated α-synuclein may be compromised in its ability to perform these functions. In addition to discussing α-synuclein structural biology, this chapter explores the variety of experimental therapeutic approaches currently under investigation that aim to maintain physiological α-synuclein levels, limit toxic aggregates, and lessen effects of misfolded α-synuclein on cellular homeostasis. For example, oligonucleotide-based approaches limit α-synuclein gene expression. In addition, select small molecules and peptides inhibit α-synuclein aggregation at substoichiometric concentrations in favor of less structured, more soluble, and less toxic oligomers that may be better substrates for clearance. Some small molecules also remodel existing α-synuclein fibrils. Modest chemical changes to these small molecules can greatly impact their mechanism of action. Finally, α-synuclein-directed immunotherapy enhances the lysosomal clearance of α-synuclein in experimental models and is currently in clinical trials. Other therapeutic approaches target α-synuclein posttranslational modifications, aim to limit its impact on mitochondria or its ability to alter gene expression in the nucleus.

show abstract

Section: Dopamine-modified α-Synuclein: Pathogen or Innocentmentioning

confidence: 55%

Targeting α-Synuclein as a Parkinson’s Disease Therapeutic

Esposito

2014

Topics in Medicinal Chemistry

View full text Add to dashboard Cite

show abstract

“…We use ␣-synuclein, the disease protein of Parkinson disease, as an example, which is significantly larger than A␤ and adopts more extended conformations in solution (93). Despite large differences in sequence properties, monomeric ensembles, and oligomer distributions, there exists a comparable range of compounds possessing one or more aromatic moieties that have been shown to bind monomeric ␣-synuclein (94) and to interfere with ␣-synuclein aggregation (53,(95)(96)(97)(98) and oligomerization (99,100). It is not necessary and perhaps unlikely that all of these inhibitors act in equivalent fashion for diverse systems.…”

Section: Discussionmentioning

confidence: 99%

Disordered Binding of Small Molecules to Aβ(12–28)

Convertino

Vitalis

Caflisch

2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Inhibition of pathogenic protein aggregation by small molecules is poorly understood. Results: Aggregation inhibitors alter the free energy landscape of a relevant fragment of Alzheimer amyloid-␤ peptide in subtle but complex fashion. Conclusion: Intrinsic disorder of disease proteins persists at the level of binding small molecules. Significance: Hallmark characteristics and efficacy of inhibitors can be reconciled with lack of specificity.

show abstract

“…Experimental evidence [9,[33][34][35] exists for metal ions binding to alpha-synuclein that seems to support this hypothesis, and further simulations are necessary to investigate this possibility. Evidence also exists for modulation of alpha-synuclein conformation by other molecules such as dopamine derivatives [36] and pesticides [37][38][39][40], and a molecular docking-MD study is underway to investigate these effects. Simulations involving multiple alpha-synuclein molecules are also needed to investigate whether the conformational changes necessary to promote aggregation are induced by the presence of other alpha-synuclein molecules, and how many are necessary to promote aggregation.…”

Section: Discussionmentioning

confidence: 99%

Unfolded annealing molecular dynamics conformers for wild-type and disease-associated variants of alpha-synuclein show no propensity for beta-sheetformation

Balesh¹,

Ramjan²,

Floriano³

2011

JBPC

View full text Add to dashboard Cite

Aggregation of alpha-synuclein leads to the formation of Lewy bodies in the brains of patients affected by Parkinson's disease (PD). Native human alpha-synuclein is unfolded in solution but assumes a partial alpha-helical conformation upon transient binding to lipid membranes. Annealing Molecular Dynamics (AMD) was used to generate a diverse set of unfolded conformers of free monomeric wild-type alpha-synuclein and PD-associated mutants A30P and A53T. The AMD conformers were compared in terms of secondary structure, hydrogen bond network, solvent-accessible surface per residue, and molecular volume. The objective of these simulations was to identify structural properties near mutation sites and the non-amyloid component (NAC) region that differ between wildtype and disease-associated variants and may be associated to aggregation of alpha-synuclein. Based on experimental evidence, a hypothesis exists that aggregation involves the formation of intermolecular beta sheets. According to our results, disease-associated mutants of alphasynuclein are no more propense to contain extended beta regions than wild-type alpha-synuclein. Moreover, extended beta structures (necessary for beta sheet formation) were not found at or around positions 30 and 53, or the NAC region in any unfolded conformer of wild-type, A30P or A53T alpha-synuclein, under the conditions of the simulations. These results do not support the hypothesis that the mutant's higher propensity to aggregation results solely from changes in amino acid sequence leading to changes in secondary structure folding propensity.

show abstract

Modulation of Alpha-Synuclein Aggregation by Dopamine Analogs

Cited by 54 publications

References 44 publications

Targeting α-Synuclein as a Parkinson’s Disease Therapeutic

Targeting α-Synuclein as a Parkinson’s Disease Therapeutic

Disordered Binding of Small Molecules to Aβ(12–28)

Unfolded annealing molecular dynamics conformers for wild-type and disease-associated variants of alpha-synuclein show no propensity for beta-sheetformation

Contact Info

Product

Resources

About