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Multistep Inhibition of alpha-Synuclein Aggregation and Toxicity in Vitro and in Vivo by Trodusquemine

Perni, M., Flagmeier, P., Limbocker, R., Cascella, R., Aprile, F. A., Galvagnion, C., Heller, G. T., Meisl, G., Chen, S. W., Kumita, J. R., Challa, P. K., Kirkegaard, J. B., Cohen, S. I. A., Mannini, B., Barbut, D., Nollen, E. A. A., Cecchi, C., Cremades, N., Knowles, T. P. J., Chiti, F., Zasloff, M., Vendruscolo, M. & Dobson, C. M., Aug-2018, In : ACS chemical biology. 13, 8, p. 2308-2319 12 p.

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  • Multistep Inhibition of α-Synuclein Aggregation and Toxicity in Vitro and in Vivo by Trodusquemine

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  • Michele Perni
  • Patrick Flagmeier
  • Ryan Limbocker
  • Roberta Cascella
  • Francesco A. Aprile
  • Celine Galvagnion
  • Gabriella T. Heller
  • Georg Meisl
  • Serene W. Chen
  • Janet R. Kumita
  • Pavan K. Challa
  • Julius B. Kirkegaard
  • Samuel I. A. Cohen
  • Benedetta Mannini
  • Denise Barbut
  • Ellen A. A. Nollen
  • Cristina Cecchi
  • Nunilo Cremades
  • Tuomas P. J. Knowles
  • Fabrizio Chiti
  • Michael Zasloff
  • Michele Vendruscolo
  • Christopher M. Dobson

The aggregation of alpha-synuclein, an intrinsically disordered protein that is highly abundant in neurons, is closely associated with the onset and progression of Parkinson's disease. We have shown previously that the aminosterol squalamine can inhibit the lipid induced initiation process in the aggregation of alpha-synuclein, and we report here that the related compound trodusquemine is capable of inhibiting not only this process but also the fibril-dependent secondary pathways in the aggregation reaction. We further demonstrate that trodusquemine can effectively suppress the toxicity of alpha-synuclein oligomers in neuronal cells, and that its administration, even after the initial growth phase, leads to a dramatic reduction in the number of alpha-synuclein inclusions in a Caenorhabditis elegans model of Parkinson's disease, eliminates the related muscle paralysis, and increases lifespan. On the basis of these findings, we show that trodusquemine is able to inhibit multiple events in the aggregation process of alpha-synuclein and hence to provide important information about the link between such events and neurodegeneration, as it is initiated and progresses. Particularly in the light of the previously reported ability of trodusquemine to cross the blood-brain barrier and to promote tissue regeneration, the present results suggest that this compound has the potential to be an important therapeutic candidate for Parkinson's disease and related disorders.

Original languageEnglish
Pages (from-to)2308-2319
Number of pages12
JournalACS chemical biology
Volume13
Issue number8
Early online date28-Jun-2018
Publication statusPublished - Aug-2018

    Keywords

  • SOLID-STATE NMR, PARKINSONS-DISEASE, CAENORHABDITIS-ELEGANS, FIBRIL FORMATION, AMPLIFICATION STEPS, BETA-SYNUCLEIN, C-ELEGANS, LIFE-SPAN, SPECTROSCOPY, INITIATION

ID: 62484167