Squalamine and Its Derivatives Modulate the Aggregation of Amyloid-β and α-Synuclein and Suppress the Toxicity of Their Oligomers

The aberrant aggregation of proteins is a key molecular event in the development and progression of a wide range of neurodegenerative disorders. We have shown previously that squalamine and trodusquemine, two natural products in the aminosterol class, can modulate the aggregation of the amyloid-β peptide (Aβ) and of α-synuclein (αS), which are associated with Alzheimer’s and Parkinson’s diseases. In this work, we expand our previous analyses to two squalamine derivatives, des-squalamine and α-squalamine, obtaining further insights into the mechanism by which aminosterols modulate Aβ and αS aggregation. We then characterize the ability of these small molecules to alter the physicochemical properties of stabilized oligomeric species in vitro and to suppress the toxicity of these aggregates to varying degrees toward human neuroblastoma cells. We found that, despite the fact that these aminosterols exert opposing effects on Aβ and αS aggregation under the conditions that we tested, the modifications that they induced to the toxicity of oligomers were similar. Our results indicate that the suppression of toxicity is mediated by the displacement of toxic oligomeric species from cellular membranes by the aminosterols. This study, thus, provides evidence that aminosterols could be rationally optimized in drug discovery programs to target oligomer toxicity in Alzheimer’s and Parkinson’s diseases.

[1]  A. Sickmann,et al.  eIF5A hypusination, boosted by dietary spermidine, protects from premature brain aging and mitochondrial dysfunction. , 2021, Cell reports.

[2]  H. Tilg,et al.  Dietary spermidine improves cognitive function. , 2021, Cell reports.

[3]  Romain F. Laine,et al.  Comparative Studies in the A30P and A53T α-Synuclein C. elegans Strains to Investigate the Molecular Origins of Parkinson's Disease , 2021, Frontiers in Cell and Developmental Biology.

[4]  M. Vendruscolo,et al.  Quantifying misfolded protein oligomers as drug targets and biomarkers in Alzheimer and Parkinson diseases , 2021, Nature Reviews Chemistry.

[5]  M. Vendruscolo,et al.  Therapeutic Strategies to Reduce the Toxicity of Misfolded Protein Oligomers , 2020, International journal of molecular sciences.

[6]  M. Vendruscolo,et al.  Making biological membrane resistant to the toxicity of misfolded protein oligomers: a lesson from trodusquemine. , 2020, Nanoscale.

[7]  D. Otzen,et al.  Inhibitors of α-Synuclein fibrillation and oligomer toxicity in Rosa damascena: the all-pervading powers of flavonoids and phenolic glycosides. , 2020, ACS chemical neuroscience.

[8]  C. Dobson,et al.  Trodusquemine displaces protein misfolded oligomers from cell membranes and abrogates their cytotoxicity through a generic mechanism , 2020, Communications Biology.

[9]  C. Dobson,et al.  Rationally Designed Antibodies as Research Tools to Study the Structure–Toxicity Relationship of Amyloid-β Oligomers , 2020, International journal of molecular sciences.

[10]  A. Šarić,et al.  Dynamics of oligomer populations formed during the aggregation of Alzheimer’s Aβ42 peptide , 2020, bioRxiv.

[11]  C. Dobson,et al.  Probing the Origin of the Toxicity of Oligomeric Aggregates of α-Synuclein with Antibodies , 2019, ACS chemical biology.

[12]  C. Dobson,et al.  Trodusquemine enhances Aβ42 aggregation but suppresses its toxicity by displacing oligomers from cell membranes , 2019, Nature Communications.

[13]  C. Dobson,et al.  SAR by kinetics for drug discovery in protein misfolding diseases , 2018, Proceedings of the National Academy of Sciences.

[14]  C. Dobson,et al.  Microfluidic deposition for resolving single-molecule protein architecture and heterogeneity , 2018, Nature Communications.

[15]  C. Dobson,et al.  Structural differences between toxic and nontoxic HypF-N oligomers. , 2018, Chemical communications.

[16]  C. Dobson,et al.  Stabilization and Characterization of Cytotoxic Aβ40 Oligomers Isolated from an Aggregation Reaction in the Presence of Zinc Ions. , 2018, ACS chemical neuroscience.

[17]  J. B. Kirkegaard,et al.  Multistep Inhibition of α-Synuclein Aggregation and Toxicity in Vitro and in Vivo by Trodusquemine. , 2018, ACS chemical biology.

[18]  C. Dobson,et al.  Cholesterol catalyses Aβ42 aggregation through a heterogeneous nucleation pathway in the presence of lipid membranes , 2018, Nature Chemistry.

[19]  C. Dobson,et al.  Structural basis of membrane disruption and cellular toxicity by α-synuclein oligomers , 2017, Science.

[20]  C. Dobson,et al.  Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade. , 2017, Annual review of biochemistry.

[21]  Michele Vendruscolo,et al.  Selective targeting of primary and secondary nucleation pathways in Aβ42 aggregation using a rational antibody scanning method , 2017, Science Advances.

[22]  T. Rando,et al.  The protein tyrosine phosphatase 1B inhibitor MSI-1436 stimulates regeneration of heart and multiple other tissues , 2017, npj Regenerative Medicine.

[23]  Michele Vendruscolo,et al.  A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity , 2017, Proceedings of the National Academy of Sciences.

[24]  Zhefeng Guo,et al.  Thioflavin T as an amyloid dye: fibril quantification, optimal concentration and effect on aggregation , 2017, Royal Society Open Science.

[25]  Tuomas P. J. Knowles,et al.  Systematic development of small molecules to inhibit specific microscopic steps of Aβ42 aggregation in Alzheimer’s disease , 2016, Proceedings of the National Academy of Sciences.

[26]  C. Dobson,et al.  Binding affinity of amyloid oligomers to cellular membranes is a generic indicator of cellular dysfunction in protein misfolding diseases , 2016, Scientific Reports.

[27]  Alexander K. Buell,et al.  Mutations associated with familial Parkinson’s disease alter the initiation and amplification steps of α-synuclein aggregation , 2016, Proceedings of the National Academy of Sciences.

[28]  H. Lashuel,et al.  Nanoscale studies link amyloid maturity with polyglutamine diseases onset , 2016, Scientific Reports.

[29]  Alexander K. Buell,et al.  Chemical properties of lipids strongly affect the kinetics of the membrane-induced aggregation of α-synuclein , 2016, Proceedings of the National Academy of Sciences.

[30]  C. Dobson,et al.  Effect of molecular chaperones on aberrant protein oligomers in vitro: super-versus sub-stoichiometric chaperone concentrations , 2016, Biological chemistry.

[31]  Michele Vendruscolo,et al.  An anticancer drug suppresses the primary nucleation reaction that initiates the production of the toxic Aβ42 aggregates linked with Alzheimer’s disease , 2016, Science Advances.

[32]  M. C. Graber,et al.  Stabilization of α-Synuclein Fibril Clusters Prevents Fragmentation and Reduces Seeding Activity and Toxicity. , 2016, Biochemistry.

[33]  C. Dobson,et al.  Structural characterization of toxic oligomers that are kinetically trapped during α-synuclein fibril formation , 2015, Proceedings of the National Academy of Sciences.

[34]  C. Dobson,et al.  Lipid vesicles trigger α-synuclein aggregation by stimulating primary nucleation. , 2015, Nature chemical biology.

[35]  Giovanni Dietler,et al.  Influence of the β-sheet content on the mechanical properties of aggregates during amyloid fibrillization. , 2015, Angewandte Chemie.

[36]  Michele Vendruscolo,et al.  The molecular chaperone Brichos breaks the catalytic cycle that generates toxic Aβ oligomers , 2015, Nature Structural &Molecular Biology.

[37]  C. Dobson,et al.  Toxicity of protein oligomers is rationalized by a function combining size and surface hydrophobicity. , 2014, ACS chemical biology.

[38]  J. Cummings,et al.  Alzheimer’s disease drug-development pipeline: few candidates, frequent failures , 2014, Alzheimer's Research & Therapy.

[39]  Tuomas P. J. Knowles,et al.  The amyloid state and its association with protein misfolding diseases , 2014, Nature Reviews Molecular Cell Biology.

[40]  Daniel H. Miller,et al.  Targeting the disordered C-terminus of PTP1B with an allosteric inhibitor , 2014, Nature chemical biology.

[41]  Michele Vendruscolo,et al.  Solution conditions determine the relative importance of nucleation and growth processes in α-synuclein aggregation , 2014, Proceedings of the National Academy of Sciences.

[42]  Michele Vendruscolo,et al.  Chemical kinetics for drug discovery to combat protein aggregation diseases. , 2014, Trends in pharmacological sciences.

[43]  Michele Vendruscolo,et al.  Proliferation of amyloid-β42 aggregates occurs through a secondary nucleation mechanism , 2013, Proceedings of the National Academy of Sciences.

[44]  Michele Vendruscolo,et al.  From macroscopic measurements to microscopic mechanisms of protein aggregation. , 2012, Journal of molecular biology.

[45]  F. Chiti,et al.  Protein misfolded oligomers: experimental approaches, mechanism of formation, and structure-toxicity relationships. , 2012, Chemistry & biology.

[46]  J. Dordick,et al.  Aromatic Small Molecules Remodel Toxic Soluble Oligomers of Amyloid β through Three Independent Pathways* , 2010, The Journal of Biological Chemistry.

[47]  M. Roitman,et al.  Inhibition of PTP1B by Trodusquemine (MSI‐1436) Causes Fat‐specific Weight Loss in Diet‐induced Obese Mice , 2010, Obesity.

[48]  Fabrizio Chiti,et al.  A causative link between the structure of aberrant protein oligomers and their toxicity. , 2010, Nature chemical biology.

[49]  C. Dobson Protein folding and misfolding , 2003, Nature.

[50]  V. Subramaniam,et al.  Dependence of α-synuclein aggregate morphology on solution conditions , 2002 .

[51]  R. Ahima,et al.  Appetite suppression and weight reduction by a centrally active aminosterol. , 2002, Diabetes.

[52]  T. Morgan,et al.  Vaccination with soluble Aβ oligomers generates toxicity‐neutralizing antibodies , 2001, Journal of neurochemistry.

[53]  T. L. Chao,et al.  Aminosterols from the dogfish shark Squalus acanthias. , 2000, Journal of natural products.

[54]  A. Elson,et al.  Protein-tyrosine Phosphatase ϵ , 1995, The Journal of Biological Chemistry.

[55]  F. Chiti,et al.  Soluble Oligomers Require a Ganglioside to Trigger Neuronal Calcium Overload. , 2017, Journal of Alzheimer's disease : JAD.

[56]  D. Selkoe Alzheimer's disease. , 2011, Cold Spring Harbor perspectives in biology.