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The Stimulatory Effects of Intracellular α-Synuclein on Synaptic Transmission Are Attenuated by 2-Octahydroisoquinolin-2(1H)-ylethanamine.
Ramirez, Alejandra E; Fernández-Pérez, Eduardo J; Olivos, Nicol; Burgos, Carlos F; Boopathi, Subramanian; Armijo-Weingart, Lorena; Pacheco, Carla R; González, Wendy; Aguayo, Luis G.
Afiliación
  • Ramirez AE; Laboratory of Neurophysiology, Department of Physiology, Faculty of Biological Sciences, Universidad de Concepción, 160-C, Concepción 4030000, Chile.
  • Fernández-Pérez EJ; Laboratory of Neurophysiology, Department of Physiology, Faculty of Biological Sciences, Universidad de Concepción, 160-C, Concepción 4030000, Chile.
  • Olivos N; Laboratory of Neurophysiology, Department of Physiology, Faculty of Biological Sciences, Universidad de Concepción, 160-C, Concepción 4030000, Chile.
  • Burgos CF; Laboratory of Neurophysiology, Department of Physiology, Faculty of Biological Sciences, Universidad de Concepción, 160-C, Concepción 4030000, Chile.
  • Boopathi S; Instituto de Ciencias Físicas, Universidad Nacional Autónoma de México, Cuernavaca 62210, Mexico.
  • Armijo-Weingart L; Center for Bioinformatics, Simulations and Modeling, The Center for Bioinformatics and Molecular Simulations (CBSM), University of Talca, Talca 3530000, Chile.
  • Pacheco CR; Laboratory of Neurophysiology, Department of Physiology, Faculty of Biological Sciences, Universidad de Concepción, 160-C, Concepción 4030000, Chile.
  • González W; Laboratory of Neurophysiology, Department of Physiology, Faculty of Biological Sciences, Universidad de Concepción, 160-C, Concepción 4030000, Chile.
  • Aguayo LG; Center for Bioinformatics, Simulations and Modeling, The Center for Bioinformatics and Molecular Simulations (CBSM), University of Talca, Talca 3530000, Chile.
Int J Mol Sci ; 22(24)2021 Dec 09.
Article en En | MEDLINE | ID: mdl-34948050
α-Synuclein (αSyn) species can be detected in synaptic boutons, where they play a crucial role in the pathogenesis of Parkinson's Disease (PD). However, the effects of intracellular αSyn species on synaptic transmission have not been thoroughly studied. Here, using patch-clamp recordings in hippocampal neurons, we report that αSyn oligomers (αSynO), intracellularly delivered through the patch electrode, produced a fast and potent effect on synaptic transmission, causing a substantial increase in the frequency, amplitude and transferred charge of spontaneous synaptic currents. We also found an increase in the frequency of miniature synaptic currents, suggesting an effect located at the presynaptic site of the synapsis. Furthermore, our in silico approximation using docking analysis and molecular dynamics simulations showed an interaction between a previously described small anti-amyloid beta (Aß) molecule, termed M30 (2-octahydroisoquinolin-2(1H)-ylethanamine), with a central hydrophobic region of αSyn. In line with this finding, our empirical data aimed to obtain oligomerization states with thioflavin T (ThT) and Western blot (WB) indicated that M30 interfered with αSyn aggregation and decreased the formation of higher-molecular-weight species. Furthermore, the effect of αSynO on synaptic physiology was also antagonized by M30, resulting in a decrease in the frequency, amplitude, and charge transferred of synaptic currents. Overall, the present results show an excitatory effect of intracellular αSyn low molecular-weight species, not previously described, that are able to affect synaptic transmission, and the potential of a small neuroactive molecule to interfere with the aggregation process and the synaptic effect of αSyn, suggesting that M30 could be a potential therapeutic strategy for synucleinopathies.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Alfa-Sinucleína / Isoquinolinas / Neuronas Límite: Animals / Humans Idioma: En Revista: Int J Mol Sci Año: 2021 Tipo del documento: Article País de afiliación: Chile Pais de publicación: Suiza
Texto completo
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Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Alfa-Sinucleína / Isoquinolinas / Neuronas Límite: Animals / Humans Idioma: En Revista: Int J Mol Sci Año: 2021 Tipo del documento: Article País de afiliación: Chile Pais de publicación: Suiza