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

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

doi:10.1073/pnas.1610586114

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

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 KnowlesMichele Vendruscolo, Adriaan Bax, Michael Zasloff, Christopher M Dobson

126 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Proceedings of the National Academy of Sciences of the United States of America
Vol/bind	114
Udgave nummer	6
Sider (fra-til)	E1009-E1017
ISSN	0027-8424
DOI	https://doi.org/10.1073/pnas.1610586114
Status	Udgivet - 7 feb. 2017

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10.1073/pnas.1610586114

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Perni, M., Galvagnion, C., Maltsev, A., Meisl, G., Müller, M. B. D., Challa, P. K., Kirkegaard, J. B., Flagmeier, P., Cohen, S. I. A., Cascella, R., Chen, S. W., Limbocker, R., Sormanni, P., Heller, G. T., Aprile, F. A., Cremades, N., Cecchi, C., Chiti, F., Nollen, E. A. A., ... Dobson, C. M. (2017). A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity. Proceedings of the National Academy of Sciences of the United States of America, 114(6), E1009-E1017. https://doi.org/10.1073/pnas.1610586114

A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity. / Perni, Michele; Galvagnion, Céline; Maltsev, Alexander et al.
I: Proceedings of the National Academy of Sciences of the United States of America, Bind 114, Nr. 6, 07.02.2017, s. E1009-E1017.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Perni, M, Galvagnion, C, Maltsev, A, Meisl, G, Müller, MBD, Challa, PK, Kirkegaard, JB, Flagmeier, P, Cohen, SIA, Cascella, R, Chen, SW, Limbocker, R, Sormanni, P, Heller, GT, Aprile, FA, Cremades, N, Cecchi, C, Chiti, F, Nollen, EAA, Knowles, TPJ, Vendruscolo, M, Bax, A, Zasloff, M & Dobson, CM 2017, 'A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity', Proceedings of the National Academy of Sciences of the United States of America, bind 114, nr. 6, s. E1009-E1017. https://doi.org/10.1073/pnas.1610586114

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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.",

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AU - Perni, Michele

AU - Galvagnion, Céline

AU - Maltsev, Alexander

AU - Meisl, Georg

AU - Müller, Martin B D

AU - Challa, Pavan K

AU - Kirkegaard, Julius B

AU - Flagmeier, Patrick

AU - Cohen, Samuel I A

AU - Cascella, Roberta

AU - Chen, Serene W

AU - Limbocker, Ryan

AU - Sormanni, Pietro

AU - Heller, Gabriella T

AU - Aprile, Francesco A

AU - Cremades, Nunilo

AU - Cecchi, Cristina

AU - Chiti, Fabrizio

AU - Nollen, Ellen A A

AU - Knowles, Tuomas P J

AU - Vendruscolo, Michele

AU - Bax, Adriaan

AU - Zasloff, Michael

AU - Dobson, Christopher M

PY - 2017/2/7

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N2 - 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.

AB - 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.

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KW - Amino Acid Sequence

KW - Animals

KW - Animals, Genetically Modified

KW - Biological Products/chemistry

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KW - Cell Line, Tumor

KW - Cholestanols/chemistry

KW - Humans

KW - Membrane Lipids/chemistry

KW - Molecular Structure

KW - Neuroblastoma/metabolism

KW - Paresis/genetics

KW - Parkinson Disease/metabolism

KW - Protein Aggregates/drug effects

KW - Protein Aggregation, Pathological/prevention & control

KW - Protein Binding/drug effects

KW - Protein Multimerization/drug effects

KW - alpha-Synuclein/chemistry

U2 - 10.1073/pnas.1610586114

DO - 10.1073/pnas.1610586114

M3 - Journal article

C2 - 28096355

SN - 0027-8424

VL - 114

SP - E1009-E1017

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 6

ER -

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

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