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.

Trodusquemine displaces protein misfolded oligomers from cell membranes and abrogates their cytotoxicity through a generic mechanism

“…Such compounds have the potential to serve in a therapeutic capacity by targeting specifically the microscopic steps of Aβ 42 that are responsible for oligomer production and proliferation [15][16][17][18][19] . Similar strategies have been employed to identify species that inhibit oligomer formation by αS, in particular by targeting the microscopic step of fibril amplification [20][21][22] .…”

“…Despite the distinct mechanisms of the aggregation of αS and Aβ 42 and the differing effects of trodusquemine on the underlying processes, however, these effects resulted in a lower steady-state concentration of oligomers in both cases, in spite of the accelerated overall aggregation process in the case of Aβ 42 28 . Moreover, this molecule was found to suppress the toxic effects of both αS and Aβ 42 oligomers in cultured human neuroblastoma cells by markedly reducing the affinity of these aggregates for the cell membrane 20,28 . We also found that squalamine, an aminosterol comparable in structure to trodusquemine but with one less positive charge in its polyamine chain, similarly reduces the toxicity of αS oligomers to cells by their displacement from cell membranes 22 .…”

Aggregation of biologically important peptides and proteins: inhibition or acceleration depending on protein and metal ion concentrations

“…74 However, the concentration of Ca 2+ required to induce a-synuclein aggregation in free solution is far higher than that required in order to induce aggregation at a hydrophobic glass surface. 74 For a binding site of Ca 2+ , study shows that Ca 2+ binds to the C-terminal domain (126)(127)(128)(129)(130)(131)(132)(133)(134)(135)(136)(137)(138)(139)(140) however, currently there is no information which particular residue is involved in the binding process. 74 There is currently a lack of information about the effect of Pb on aggregation in vitro, although it has been demonstrated that Zn 2+ , Al 3+ and Pb 2+ enable methionineoxidized a-synuclein, 75 to form aggregates at the same rate as the non-oxidized a-synuclein.…”

“…Understanding how protein aggregation works has led some scientists to develop anti-aggregation drugs against TP and a-synuclein. [134][135][136] More systematic experiments designed to clarify this relationship are vital, as they may provide the groundwork to produce better therapeutics. Therefore, further research with more rigorous and detailed studies are necessary to denitively uncover the relationship between metal ions and their effects on the aggregation of proteins, with a particular emphasis on their concentrations and relative ratios.…”

Targeting Amyloid Aggregation: An Overview of Strategies and Mechanisms

“…Recently, a squalamine derivative, called trodusquemine, has been shown to affect the aggregation of α-syn as well [ 36 ]. In addition to displacing α-syn monomers similar to the mechanism fulfilled by squalamine, trodusquemine directly interacts with α-syn to inhibit the secondary nucleation of aggregation [ 36 ].…”