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

Abstract

The self-assembly of α-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 α-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 α-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 α-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 α-synuclein, observing a dramatic reduction of α-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.

• Authors: Michele Perni, Céline Galvagnion, Alexander Maltsev, Georg Meisl, Martin B D Müller, Pavan K Challa, Julius B Kirkegaard, Patrick Flagmeier, Samuel I A Cohen, Roberta Cascella, Serene W Chen, Ryan Limbocker, 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
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 114 Issue 6 Pg. E1009-E1017 (02 07 2017) ISSN: 1091-6490 [Electronic] United States
• PMID: 28096355 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biological Products
• Cholestanols
• Membrane Lipids
• Protein Aggregates
• alpha-Synuclein
• squalamine

Topics

• Algorithms
• Amino Acid Sequence
• Animals
• Animals, Genetically Modified
• Biological Products (chemistry, pharmacology)
• Caenorhabditis elegans (genetics, metabolism)
• Cell Line, Tumor
• Cholestanols (chemistry, pharmacology)
• Humans
• Membrane Lipids (chemistry, metabolism)
• Molecular Structure
• Neuroblastoma (metabolism, pathology)
• Paresis (genetics, metabolism, prevention & control)
• Parkinson Disease (metabolism)
• Protein Aggregates (drug effects)
• Protein Aggregation, Pathological (prevention & control)
• Protein Binding (drug effects)
• Protein Multimerization (drug effects)
• alpha-Synuclein (chemistry, genetics, metabolism)