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.

Multistep Inhibition of α‑Synuclein Aggregation and Toxicity in Vitro and in Vivo by Trodusquemine / 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. - In: ACS CHEMICAL BIOLOGY. - ISSN 1554-8929. - STAMPA. - 13:(2018), pp. 2308-2319. [10.1021/acschembio.8b00466]

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

Cascella R;Mannini B;Cecchi C;Chiti F;
2018

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.
2018
13
2308
2319
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, M...espandi
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1132660
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