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

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Standard

A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity. / Perni, Michele; Galvagnion, Céline; Maltsev, Alexander; Meisl, Georg; Müller, Martin B D; Challa, Pavan K; Kirkegaard, Julius B; Flagmeier, Patrick; Cohen, Samuel I A; Cascella, Roberta; Chen, Serene W; Limbocker, Ryan; Sormanni, Pietro; Heller, Gabriella T; Aprile, Francesco A; Cremades, Nunilo; Cecchi, Cristina; Chiti, Fabrizio; Nollen, Ellen A A; Knowles, Tuomas P J; Vendruscolo, Michele; Bax, Adriaan; Zasloff, Michael; Dobson, Christopher M.

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 › fagfællebedømt

Harvard

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

APA

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

Vancouver

Perni M, Galvagnion C, Maltsev A, Meisl G, Müller MBD, Challa PK o.a. 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. 2017 feb. 7;114(6):E1009-E1017. https://doi.org/10.1073/pnas.1610586114

Author

Perni, Michele ; Galvagnion, Céline ; Maltsev, Alexander ; Meisl, Georg ; Müller, Martin B D ; Challa, Pavan K ; Kirkegaard, Julius B ; Flagmeier, Patrick ; Cohen, Samuel I A ; Cascella, Roberta ; Chen, Serene W ; Limbocker, Ryan ; Sormanni, Pietro ; Heller, Gabriella T ; Aprile, Francesco A ; Cremades, Nunilo ; Cecchi, Cristina ; Chiti, Fabrizio ; Nollen, Ellen A A ; Knowles, Tuomas P J ; Vendruscolo, Michele ; Bax, Adriaan ; Zasloff, Michael ; Dobson, Christopher M. / A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity. I: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Bind 114, Nr. 6. s. E1009-E1017.

Bibtex

@article{66f5d50bc4dc4871aa17b0b795c35b1e,
title = "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.",
keywords = "Algorithms, Amino Acid Sequence, Animals, Animals, Genetically Modified, Biological Products/chemistry, Caenorhabditis elegans/genetics, Cell Line, Tumor, Cholestanols/chemistry, Humans, Membrane Lipids/chemistry, Molecular Structure, Neuroblastoma/metabolism, Paresis/genetics, Parkinson Disease/metabolism, Protein Aggregates/drug effects, Protein Aggregation, Pathological/prevention & control, Protein Binding/drug effects, Protein Multimerization/drug effects, alpha-Synuclein/chemistry",
author = "Michele Perni and C{\'e}line Galvagnion and Alexander Maltsev and Georg Meisl and M{\"u}ller, {Martin B D} and Challa, {Pavan K} and Kirkegaard, {Julius B} and Patrick Flagmeier and Cohen, {Samuel I A} and Roberta Cascella and Chen, {Serene W} and Ryan Limbocker and Pietro Sormanni and Heller, {Gabriella T} and Aprile, {Francesco A} and Nunilo Cremades and Cristina Cecchi and Fabrizio Chiti and Nollen, {Ellen A A} and Knowles, {Tuomas P J} and Michele Vendruscolo and Adriaan Bax and Michael Zasloff and Dobson, {Christopher M}",
year = "2017",
month = feb,
day = "7",
doi = "10.1073/pnas.1610586114",
language = "English",
volume = "114",
pages = "E1009--E1017",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "The National Academy of Sciences of the United States of America",
number = "6",

}

RIS

TY - JOUR

T1 - A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity

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

Y1 - 2017/2/7

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.

KW - Algorithms

KW - Amino Acid Sequence

KW - Animals

KW - Animals, Genetically Modified

KW - Biological Products/chemistry

KW - Caenorhabditis elegans/genetics

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

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

SN - 0027-8424

IS - 6

ER -

ID: 216263486