Inhibition of α-synuclein fibrillization by dopamine is mediated by interactions with five C-terminal residues and with E83 in the NAC region

Fernando E. Herrera, Alessandra Chesi, Katerina E. Paleologou, Adrian Schmid, Adriana Munoz, Michele Vendruscolo, Stefano Gustincich, Hilal A. Lashuel, Paolo Carloni

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

The interplay between dopamine and α-synuclein (AS) plays a central role in Parkinson's disease (PD). PD results primarily from a severe and selective devastation of dopaminergic neurons in substantia nigra pars compacta. The neuropathological hallmark of the disease is the presence of intraneuronal proteinaceous inclusions known as Lewy bodies within the surviving neurons, enriched in filamentous AS. In vitro, dopamine inhibits AS fibril formation, but the molecular determinants of this inhibition remain obscure. Here we use molecular dynamic (MD) simulations to investigate the binding of dopamine and several of its derivatives onto conformers representative of an NMR ensemble of AS structures in aqueous solution. Within the limitations inherent to MD simulations of unstructured proteins, our calculations suggest that the ligands bind to the 125YEMPS129 region, consistent with experimental findings. The ligands are further stabilized by long-range electrostatic interactions with glutamate 83 (E83) in the NAC region. These results suggest that by forming these interactions with AS, dopamine may affect AS aggregation and fibrillization properties. To test this hypothesis, we investigated in vitro the effects of dopamine on the aggregation of mutants designed to alter or abolish these interactions. We found that point mutations in the 125YEMPS129 region do not affect AS aggregation, which is consistent with the fact that dopamine interacts non-specifically with this region. In contrast, and consistent with our modeling studies, the replacement of glutamate by alanine at position 83 (E83A) abolishes the ability of dopamine to inhibit AS fibrillization.

Original languageEnglish
Article numbere3394
JournalPLoS One
Volume3
Issue number10
DOIs
Publication statusPublished - 14 Oct 2008
Externally publishedYes

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Synucleins
dopamine
Dopamine
molecular dynamics
Parkinson disease
Agglomeration
glutamates
Molecular Dynamics Simulation
Neurons
Parkinson Disease
Molecular dynamics
neurons
Glutamic Acid
Intrinsically Disordered Proteins
Ligands
electrostatic interactions
Lewy Bodies
point mutation
Dopaminergic Neurons
Computer simulation

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Herrera, F. E., Chesi, A., Paleologou, K. E., Schmid, A., Munoz, A., Vendruscolo, M., ... Carloni, P. (2008). Inhibition of α-synuclein fibrillization by dopamine is mediated by interactions with five C-terminal residues and with E83 in the NAC region. PLoS One, 3(10), [e3394]. https://doi.org/10.1371/journal.pone.0003394

Inhibition of α-synuclein fibrillization by dopamine is mediated by interactions with five C-terminal residues and with E83 in the NAC region. / Herrera, Fernando E.; Chesi, Alessandra; Paleologou, Katerina E.; Schmid, Adrian; Munoz, Adriana; Vendruscolo, Michele; Gustincich, Stefano; Lashuel, Hilal A.; Carloni, Paolo.

In: PLoS One, Vol. 3, No. 10, e3394, 14.10.2008.

Research output: Contribution to journalArticle

Herrera, FE, Chesi, A, Paleologou, KE, Schmid, A, Munoz, A, Vendruscolo, M, Gustincich, S, Lashuel, HA & Carloni, P 2008, 'Inhibition of α-synuclein fibrillization by dopamine is mediated by interactions with five C-terminal residues and with E83 in the NAC region', PLoS One, vol. 3, no. 10, e3394. https://doi.org/10.1371/journal.pone.0003394
Herrera, Fernando E. ; Chesi, Alessandra ; Paleologou, Katerina E. ; Schmid, Adrian ; Munoz, Adriana ; Vendruscolo, Michele ; Gustincich, Stefano ; Lashuel, Hilal A. ; Carloni, Paolo. / Inhibition of α-synuclein fibrillization by dopamine is mediated by interactions with five C-terminal residues and with E83 in the NAC region. In: PLoS One. 2008 ; Vol. 3, No. 10.
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