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A natural product inhibits the initiation of alpha-synuclein aggregation and suppresses its toxicity

Perni, M., Galvagnion, C., Maltsev, A., Meisl, G., Mueller, M. B. D., Challa, P. K., Kirkegaard, J. B., Flagmeier, P., Cohen, S. I. A., Cascella, R., Chen, S. W., Limboker, R., Sormanni, P., Heller, G. T., Aprile, F. A., Cremades, N., Cecchi, C., Chiti, F., Nollen, E. A. A., Knowles, T. P. J., Vendruscolo, M., Bax, A., Zasloff, M. & Dobson, C. M., 7-Feb-2017, In : Proceedings of the National Academy of Sciences of the United States of America. 114, 6, p. E1009-E1017 9 p.

Research output: Contribution to journalArticleAcademicpeer-review

  • Michele Perni
  • Celine Galvagnion
  • Alexander Maltsev
  • Georg Meisl
  • Martin B. D. Mueller
  • Pavan K Challa
  • Julius B Kirkegaard
  • Patrick Flagmeier
  • Samuel I A Cohen
  • Roberta Cascella
  • Serene W Chen
  • Ryan Limboker
  • Pietro Sormanni
  • Gabriella T Heller
  • Francesco A Aprile
  • Nunilo Cremades
  • Cristina Cecchi
  • Fabrizio Chiti
  • Ellen A. A. Nollen
  • Tuomas P J Knowles
  • Michele Vendruscolo
  • Adriaan Bax
  • Michael Zasloff
  • Christopher M. Dobson

The self-assembly of alpha-synuclein is closely associated with Parkinson's disease and related syndromes. We show that squalamine, a natural product with known anticancer and antiviral activity, dramatically affects alpha-synuclein aggregation in vitro and in vivo. We elucidate the mechanism of action of squalamine by investigating its interaction with lipid vesicles, which are known to stimulate nucleation, and find that this compound displaces alpha-synuclein from the surfaces of such vesicles, thereby blocking the first steps in its aggregation process. We also show that squalamine almost completely suppresses the toxicity of alpha-synuclein oligomers in human neuroblastoma cells by inhibiting their interactions with lipid membranes. We further examine the effects of squalamine in a Caenorhabditis elegans strain overexpressing alpha-synuclein, observing a dramatic reduction of alpha-synuclein aggregation and an almost complete elimination of muscle paralysis. These findings suggest that squalamine could be a means of therapeutic intervention in Parkinson's disease and related conditions.

Original languageEnglish
Pages (from-to)E1009-E1017
Number of pages9
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number6
Publication statusPublished - 7-Feb-2017

    Keywords

  • Parkinson's disease, protein aggregation, amyloid formation, toxic oligomers, drug development, PROTEIN MISFOLDING DISEASES, PARKINSONS-DISEASE, CAENORHABDITIS-ELEGANS, AMPLIFICATION STEPS, NMR-SPECTROSCOPY, SURFACE-CHARGE, LEWY BODIES, SQUALAMINE, BINDING, PHOSPHORYLATION
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  1. Correction for Perni et al., A natural product inhibits the initiation of alpha-synuclein aggregation and suppresses its toxicity (vol 114, pg E1009, 2017)

    Perni, M., Galvagnion, C., Maltsev, A., Meisl, G., Mueller, M. B. D., Challa, P. K., Kirkegaard, J. B., Flagmeier, P., Cohen, S. I. A., Cascella, R., Chen, S. W., Limboker, R., Sormanni, P., Heller, G. T., Aprile, F. A., Cremades, N., Cecchi, C., Chiti, F., Nollen, E. A. A., Knowles, T. P. J., Vendruscolo, M., Bax, A., Zasloff, M. & Dobson, C. M., 21-Mar-2017, In : Proceedings of the National Academy of Science of the United States of America. 114, 12, p. E2543-E2543 1 p.

    Research output: Contribution to journalArticleAcademicpeer-review

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