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

Michele Perni; Patrick Flagmeier; Ryan Limbocker; Roberta Cascella; Francesco A Aprile; Céline 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

doi:10.1021/acschembio.8b00466

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

Michele Perni, Patrick Flagmeier, Ryan Limbocker, Roberta Cascella, Francesco A Aprile, Céline 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 ChitiMichael Zasloff, Michele Vendruscolo, Christopher M Dobson

32 Citations (Scopus)

Abstract

The aggregation of α-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 α-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 α-synuclein oligomers in neuronal cells, and that its administration, even after the initial growth phase, leads to a dramatic reduction in the number of α-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 α-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 language	English
Journal	ACS chemical biology
Volume	13
Issue number	8
Pages (from-to)	2308-2319
Number of pages	12
ISSN	1554-8929
DOIs	https://doi.org/10.1021/acschembio.8b00466
Publication status	Published - 17 Aug 2018
Externally published	Yes

Keywords

Animals
Caenorhabditis elegans/physiology
Cell Line
Cholestanes/pharmacology
Disease Models, Animal
Humans
Neurons/drug effects
Parkinson Disease/drug therapy
Protein Aggregates/drug effects
Protein Aggregation, Pathological/metabolism
Spermine/analogs & derivatives
alpha-Synuclein/metabolism

Access to Document

10.1021/acschembio.8b00466

Cite this

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., ... Dobson, C. M. (2018). Multistep Inhibition of α-Synuclein Aggregation and Toxicity in Vitro and in Vivo by Trodusquemine. ACS chemical biology, 13(8), 2308-2319. https://doi.org/10.1021/acschembio.8b00466

Perni, M, Flagmeier, P, Limbocker, R, Cascella, R, Aprile, FA, Galvagnion, C, Heller, GT, Meisl, G, Chen, SW, Kumita, JR, Challa, PK, Kirkegaard, JB, Cohen, SIA, Mannini, B, Barbut, D, Nollen, EAA, Cecchi, C, Cremades, N, Knowles, TPJ, Chiti, F, Zasloff, M, Vendruscolo, M & Dobson, CM 2018, 'Multistep Inhibition of α-Synuclein Aggregation and Toxicity in Vitro and in Vivo by Trodusquemine', ACS chemical biology, vol. 13, no. 8, pp. 2308-2319. https://doi.org/10.1021/acschembio.8b00466

@article{ea72c9f8386d4d0fb99bf70a885b5664,

title = "Multistep Inhibition of α-Synuclein Aggregation and Toxicity in Vitro and in Vivo by Trodusquemine",

abstract = "The aggregation of α-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 α-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 α-synuclein oligomers in neuronal cells, and that its administration, even after the initial growth phase, leads to a dramatic reduction in the number of α-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 α-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.",

keywords = "Animals, Caenorhabditis elegans/physiology, Cell Line, Cholestanes/pharmacology, Disease Models, Animal, Humans, Neurons/drug effects, Parkinson Disease/drug therapy, Protein Aggregates/drug effects, Protein Aggregation, Pathological/metabolism, Spermine/analogs & derivatives, alpha-Synuclein/metabolism",

author = "Michele Perni and Patrick Flagmeier and Ryan Limbocker and Roberta Cascella and Aprile, {Francesco A} and C{\'e}line Galvagnion and Heller, {Gabriella T} and Georg Meisl and Chen, {Serene W} and Kumita, {Janet R} and Challa, {Pavan K} and Kirkegaard, {Julius B} and Cohen, {Samuel I A} and Benedetta Mannini and Denise Barbut and Nollen, {Ellen A A} and Cristina Cecchi and Nunilo Cremades and Knowles, {Tuomas P J} and Fabrizio Chiti and Michael Zasloff and Michele Vendruscolo and Dobson, {Christopher M}",

year = "2018",

month = aug,

day = "17",

doi = "10.1021/acschembio.8b00466",

language = "English",

volume = "13",

pages = "2308--2319",

journal = "ACS chemical biology",

issn = "1554-8929",

publisher = "American Chemical Society",

number = "8",

}

TY - JOUR

T1 - Multistep Inhibition of α-Synuclein Aggregation and Toxicity in Vitro and in Vivo by Trodusquemine

AU - Perni, Michele

AU - Flagmeier, Patrick

AU - Limbocker, Ryan

AU - Cascella, Roberta

AU - Aprile, Francesco A

AU - Galvagnion, Céline

AU - Heller, Gabriella T

AU - Meisl, Georg

AU - Chen, Serene W

AU - Kumita, Janet R

AU - Challa, Pavan K

AU - Kirkegaard, Julius B

AU - Cohen, Samuel I A

AU - Mannini, Benedetta

AU - Barbut, Denise

AU - Nollen, Ellen A A

AU - Cecchi, Cristina

AU - Cremades, Nunilo

AU - Knowles, Tuomas P J

AU - Chiti, Fabrizio

AU - Zasloff, Michael

AU - Vendruscolo, Michele

AU - Dobson, Christopher M

PY - 2018/8/17

Y1 - 2018/8/17

N2 - The aggregation of α-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 α-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 α-synuclein oligomers in neuronal cells, and that its administration, even after the initial growth phase, leads to a dramatic reduction in the number of α-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 α-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.

AB - The aggregation of α-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 α-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 α-synuclein oligomers in neuronal cells, and that its administration, even after the initial growth phase, leads to a dramatic reduction in the number of α-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 α-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.

KW - Animals

KW - Caenorhabditis elegans/physiology

KW - Cell Line

KW - Cholestanes/pharmacology

KW - Disease Models, Animal

KW - Humans

KW - Neurons/drug effects

KW - Parkinson Disease/drug therapy

KW - Protein Aggregates/drug effects

KW - Protein Aggregation, Pathological/metabolism

KW - Spermine/analogs & derivatives

KW - alpha-Synuclein/metabolism

U2 - 10.1021/acschembio.8b00466

DO - 10.1021/acschembio.8b00466

M3 - Journal article

C2 - 29953201

SN - 1554-8929

VL - 13

SP - 2308

EP - 2319

JO - ACS chemical biology

JF - ACS chemical biology

IS - 8

ER -

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

Abstract

Keywords

Access to Document

Fingerprint

Cite this