Imperial College London

ProfessorAlfonsoDe Simone

Faculty of Natural SciencesDepartment of Life Sciences

Visiting Professor
 
 
 
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Contact

 

+44 (0)20 7594 3052a.de-simon Website

 
 
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Location

 

603Sir Ernst Chain BuildingSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
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132 results found

Manchinu MF, Pala M, Palmas MF, Diana MA, Maschio A, Etzi M, Pisanu A, Diana FI, Marongiu J, Mansueto S, Carboni E, Fusco G, De Simone A, Carta ARet al., 2024, Region-specific changes in gene expression are associated with cognitive deficits in the alpha-synuclein-induced model of Parkinson's disease: A transcriptomic profiling study., Exp Neurol, Vol: 372

Mild cognitive impairment (MCI) is a common trait of Parkinson's disease (PD), often associated with early motor deficits, eventually evolving to PD with dementia in later disease stages. The neuropathological substrate of MCI is poorly understood, which weakens the development and administration of proper therapies. In an α-synuclein (αSyn)-based model of PD featuring early motor and cognitive impairments, we investigated the transcriptome profile of brain regions involved in PD with cognitive deficits, via a transcriptomic analysis based on RNA sequencing (RNA-seq) technology. Rats infused in the substantia nigra with human α-synuclein oligomers (H-SynOs) developed mild cognitive deficits after three months, as measured by the two-trial recognition test in a Y-maze and the novel object recognition test. RNA-seq analysis showed that 17,436 genes were expressed in the anterior cingulate cortex (ACC) and 17,216 genes in the hippocampus (HC). In the ACC, 51 genes were differentially expressed between vehicle and H-αSynOs treated samples, which showed N= 21 upregulated and N = 30 downregulated genes. In the HC, 104 genes were differentially expressed, the majority of them not overlapping with DEGs in the ACC, with N = 41 upregulated and N = 63 downregulated in H-αSynOs-treated samples. The Gene Ontology (GO) and the Kyoto Encyclopedia of Gene and Genomes (KEGG) analysis, followed by the protein-protein interaction (PPI) network inspection of DEGs, revealed that in the ACC most enriched terms were related with immune functions, specifically with antigen processing/presentation via the major histocompatibility complex (MHC) class II and phagocytosis via CD68, supporting a role for dysregulated immune responses in early PD cognitive dysfunction. Immunofluorescence analysis confirmed the decreased expression of CD68 within microglial cells. In contrast, the most significantly enriched terms in the HC were mai

Journal article

Sgueglia G, Vrettas MD, Chino M, De Simone A, Lombardi Aet al., 2023, MetalHawk: Enhanced Classification of Metal Coordination Geometries by Artificial Neural Networks., J Chem Inf Model

The chemical properties of metal complexes are strongly dependent on the number and geometrical arrangement of ligands coordinated to the metal center. Existing methods for determining either coordination number or geometry rely on a trade-off between accuracy and computational costs, which hinders their application to the study of large structure data sets. Here, we propose MetalHawk (https://github.com/vrettasm/MetalHawk), a machine learning-based approach to perform simultaneous classification of metal site coordination number and geometry through artificial neural networks (ANNs), which were trained using the Cambridge Structural Database (CSD) and Metal Protein Data Bank (MetalPDB). We demonstrate that the CSD-trained model can be used to classify sites belonging to the most common coordination numbers and geometry classes with balanced accuracy equal to 96.51% for CSD-deposited metal sites. The CSD-trained model was also found to be capable of classifying bioinorganic metal sites from the MetalPDB database, with balanced accuracy equal to 84.29% on the whole PDB data set and to 91.66% on manually reviewed sites in the PDB validation set. Moreover, we report evidence that the output vectors of the CSD-trained model can be considered as a proxy indicator of metal-site distortions, showing that these can be interpreted as a low-dimensional representation of subtle geometrical features present in metal site structures.

Journal article

Mansueto S, Fusco G, De Simone A, 2023, α-Synuclein and biological membranes: the danger of loving too much, CHEMICAL COMMUNICATIONS, Vol: 59, Pages: 8769-8778, ISSN: 1359-7345

Journal article

Vassallo N, Ongeri S, De Simone A, 2023, Editorial: Oligomers in amyloid-associated diseases-structural properties and toxicity, FRONTIERS IN MOLECULAR BIOSCIENCES, Vol: 10

Journal article

Gonzalez-Garcia M, Fusco G, De Simone A, 2023, Metal interactions of α-synuclein probed by NMR amide-proton exchange, FRONTIERS IN CHEMISTRY, Vol: 11, ISSN: 2296-2646

Journal article

Qi G, Vrettas MD, Biancaniello C, Sanz-Hernandez M, Cafolla CT, Morgan JWR, Wang Y, De Simone A, Wales DJet al., 2022, Enhancing Biomolecular Simulations with Hybrid Potentials Incorporating NMR Data, JOURNAL OF CHEMICAL THEORY AND COMPUTATION, Vol: 18, Pages: 7733-7750, ISSN: 1549-9618

Journal article

Fusco G, Biancaniello C, Vrettas MD, De Simone Aet al., 2022, Thermal tuning of protein hydration in a hyperthermophilic enzyme, FRONTIERS IN MOLECULAR BIOSCIENCES, Vol: 9

Journal article

Reimer L, Gram H, Jensen NM, Betzer C, Yang L, Jin L, Shi M, Boudeffa D, Fusco G, De Simone A, Kirik D, Lashuel HA, Zhang J, Jensen PHet al., 2022, Protein kinase R dependent phosphorylation of α-synuclein regulates its membrane binding and aggregation, PNAS NEXUS, Vol: 1

Journal article

Fusco G, Bemporad F, Chiti F, Dobson CMM, De Simone Aet al., 2022, The role of structural dynamics in the thermal adaptation of hyperthermophilic enzymes, FRONTIERS IN MOLECULAR BIOSCIENCES, Vol: 9

Journal article

Palmas MF, Etzi M, Pisanu A, Camoglio C, Sagheddu C, Santoni M, Manchinu MF, Pala M, Fusco G, De Simone A, Picci L, Mulas G, Spiga S, Scherma M, Fadda P, Pistis M, Simola N, Carboni E, Carta ARet al., 2022, The Intranigral Infusion of Human-Alpha Synuclein Oligomers Induces a Cognitive Impairment in Rats Associated with Changes in Neuronal Firing and Neuroinflammation in the Anterior Cingulate Cortex, CELLS, Vol: 11

Journal article

Balasco N, Esposito L, De Simone A, Vitagliano Let al., 2022, Local Backbone Geometry Plays a Critical Role in Determining Conformational Preferences of Amino Acid Residues in Proteins, BIOMOLECULES, Vol: 12

Journal article

Malagrino F, Fusco G, Pennacchietti V, Toto A, Nardella C, Pagano L, de Simone A, Gianni Set al., 2022, Cryptic binding properties of a transient folding intermediate in a PDZ tandem repeat, PROTEIN SCIENCE, Vol: 31, ISSN: 0961-8368

Journal article

Olivieri C, Li GC, Wang Y, Manu VS, Walker C, Kim J, Camilloni C, De Simone A, Vendruscolo M, Bernlohr DA, Taylor SS, Veglia Get al., 2022, ATP-competitive inhibitors modulate the substrate binding cooperativity of a kinase by altering its conformational entropy, SCIENCE ADVANCES, Vol: 8, ISSN: 2375-2548

Journal article

Navarro-Paya C, Sanz-Hernandez M, De Simone A, 2022, Plasticity of Membrane Binding by the Central Region of α-Synuclein, FRONTIERS IN MOLECULAR BIOSCIENCES, Vol: 9

Journal article

Reddy UV, Weber DK, Wang S, Larsen EK, Gopinath T, De Simone A, Robia S, Veglia Get al., 2022, A kink in DWORF helical structure controls the activation of the sarcoplasmic reticulum Ca<SUP>2+</SUP>-ATPase, STRUCTURE, Vol: 30, Pages: 360-+, ISSN: 0969-2126

Journal article

Palmas MF, Ena A, Burgaletto C, Casu MA, Cantarella G, Carboni E, Etzi M, De Simone A, Fusco G, Cardia MC, Lai F, Picci L, Tweedie D, Scerba MT, Coroneo V, Bernardini R, Greig NH, Pisanu A, Carta ARet al., 2022, Repurposing Pomalidomide as a Neuroprotective Drug: Efficacy in an Alpha-Synuclein-Based Model of Parkinson's Disease, NEUROTHERAPEUTICS, Vol: 19, Pages: 305-324, ISSN: 1933-7213

Journal article

Weber DK, Reddy UV, Wang S, Larsen EK, Gopinath T, Gustavsson MB, Cornea RL, Thomas DD, De Simone A, Veglia Get al., 2021, Structural basis for allosteric control of the SERCA-Phospholamban membrane complex by Ca<SUP>2+</SUP> and phosphorylation, ELIFE, Vol: 10, ISSN: 2050-084X

Journal article

Sanz-Hernandez M, De Simone A, 2021, Backbone NMR assignments of the C-terminal domain of the human prion protein and its disease-associated T183A variant, BIOMOLECULAR NMR ASSIGNMENTS, Vol: 15, Pages: 193-196, ISSN: 1874-2718

Journal article

Sanz-Hernandez M, Barritt JD, Sobek J, Hornemann S, Aguzzi A, De Simone Aet al., 2021, Mechanism of misfolding of the human prion protein revealed by a pathological mutation, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 118, ISSN: 0027-8424

Journal article

Perni M, van der Goot A, Limbocker R, van Ham TJ, Aprile FA, Xu CK, Flagmeier P, Thijssen K, Sormanni P, Fusco G, Chen SW, Challa PK, Kirkegaard JB, Laine RF, Ma KY, Muller MBD, Sinnige T, Kumita JR, Cohen SIA, Seinstra R, Kaminski Schierle GS, Kaminski CF, Barbut D, De Simone A, Knowles TPJ, Zasloff M, Nollen EAA, Vendruscolo M, Dobson CMet al., 2021, Comparative studies in the A30P and A53T alpha-Synuclein C. elegans strains to investigate the molecular origins of Parkinson's Disease, Frontiers in Cell and Developmental Biology, Vol: 9, Pages: 1-10, ISSN: 2296-634X

The aggregation of α-synuclein is a hallmark of Parkinson's disease (PD) and a variety of related neurological disorders. A number of mutations in this protein, including A30P and A53T, are associated with familial forms of the disease. Patients carrying the A30P mutation typically exhibit a similar age of onset and symptoms as sporadic PD, while those carrying the A53T mutation generally have an earlier age of onset and an accelerated progression. We report two C. elegans models of PD (PDA30P and PDA53T), which express these mutational variants in the muscle cells, and probed their behavior relative to animals expressing the wild-type protein (PDWT). PDA30P worms showed a reduced speed of movement and an increased paralysis rate, control worms, but no change in the frequency of body bends. By contrast, in PDA53T worms both speed and frequency of body bends were significantly decreased, and paralysis rate was increased. α-Synuclein was also observed to be less well localized into aggregates in PDA30P worms compared to PDA53T and PDWT worms, and amyloid-like features were evident later in the life of the animals, despite comparable levels of expression of α-synuclein. Furthermore, squalamine, a natural product currently in clinical trials for treating symptomatic aspects of PD, was found to reduce significantly the aggregation of α-synuclein and its associated toxicity in PDA53T and PDWT worms, but had less marked effects in PDA30P. In addition, using an antibody that targets the N-terminal region of α-synuclein, we observed a suppression of toxicity in PDA30P, PDA53T and PDWT worms. These results illustrate the use of these two C. elegans models in fundamental and applied PD research.

Journal article

Gonzalez-Garcia M, Fusco G, De Simone A, 2021, Membrane interactions and toxicity by misfolded protein oligomers, Frontiers in Cell and Developmental Biology, Vol: 9, Pages: 1-12, ISSN: 2296-634X

The conversion of otherwise soluble proteins into insoluble amyloid aggregates is associated with a range of neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases, as well as non-neuropathic conditions such as type II diabetes and systemic amyloidoses. It is increasingly evident that the most pernicious species among those forming during protein aggregation are small prefibrillar oligomers. In this review, we describe the recent progress in the characterization of the cellular and molecular interactions by toxic misfolded protein oligomers. A fundamental interaction by these aggregates involves biological membranes, resulting in two major model mechanisms at the onset of the cellular toxicity. These include the membrane disruption model, resulting in calcium imbalance, mitochondrial dysfunction and intracellular reactive oxygen species, and the direct interaction with membrane proteins, leading to the alteration of their native function. A key challenge remains in the characterization of transient interactions involving heterogeneous protein aggregates. Solving this task is crucial in the quest of identifying suitable therapeutic approaches to suppress the cellular toxicity in protein misfolding diseases.

Journal article

Nguyen PH, Ramamoorthy A, Sahoo BR, Zheng J, Faller P, Straub JE, Dominguez L, Shea J-E, Dokholyan N, De Simone A, Ma B, Nussinov R, Najafi S, Ngo ST, Loquet A, Chiricotto M, Ganguly P, McCarty J, Li MS, Hall C, Wang Y, Miller Y, Melchionna S, Habenstein B, Timr S, Chen J, Hnath B, Strodel B, Kayed R, Lesne S, Wei G, Sterpone F, Doig AJ, Derreumaux Pet al., 2021, Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer's Disease, Parkinson's Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis, CHEMICAL REVIEWS, Vol: 121, Pages: 2545-2647, ISSN: 0009-2665

Journal article

Man W, Tahirbegi B, Vrettas M, Ying L, Vendruscolo M, De Simone A, Fusco Get al., 2021, The docking of synaptic vesicles on the presynaptic membrane induced by α-synuclein is modulated by lipid composition, Nature Communications, Vol: 12, ISSN: 2041-1723

α-Synuclein (αS) is a presynaptic disordered protein whose aberrant aggregation is associated with Parkinson’s disease. The functional role of αS is still debated, although it has been involved in the regulation of neurotransmitter release via the interaction with synaptic vesicles (SVs). We report here a detailed characterisation of the conformational properties of αS bound to the inner and outer leaflets of the presynaptic plasma membrane (PM), using small unilamellar vesicles. Our results suggest that αS preferentially binds the inner PM leaflet. On the basis of these studies we characterise in vitro a mechanism by which αS stabilises, in a concentration-dependent manner, the docking of SVs on the PM by establishing a dynamic link between the two membranes. The study then provides evidence that changes in the lipid composition of the PM, typically associated with neurodegenerative diseases, alter the modes of binding of αS, specifically in a segment of the sequence overlapping with the non-amyloid component region. Taken together, these results reveal how lipid composition modulates the interaction of αS with the PM and underlie its functional and pathological behaviours in vitro.

Journal article

O'Brien HER, Zhang XF, Sanz-Hernandez M, Chion A, Shapiro S, Mobayen G, Xu Y, De Simone A, Laffan MA, McKinnon TAJet al., 2021, Blocking von Willebrand factor free thiols inhibits binding to collagen under high and pathological shear stress, Journal of Thrombosis and Haemostasis, Vol: 19, Pages: 358-369, ISSN: 1538-7836

BackgroundVon Willebrand factor (VWF) contains a number of free thiols, the majority of which are located in its C‐domains, and these have been shown to alter VWF function, However, the impact of free thiols on function following acute exposure of VWF to collagen under high and pathological shear stress has not been determined.MethodsVWF free thiols were blocked with N‐ethylmaleimide and flow assays performed under high and pathological shear rates to determine the impact on platelet capture and collagen binding function. Atomic force microscopy (AFM) was used to probe the interaction of VWF with collagen and molecular simulations conducted to determine the effect of free thiols on the flexibility of the VWF‐C4 domain.ResultsBlockade of VWF free thiols reduced VWF‐mediated platelet capture to collagen in a shear‐dependent manner, with platelet capture virtually abolished above 5000 s−1 and in regions of stenosis in microfluidic channels. Direct visualization of VWF fibers formed under extreme pathological shear rates and analysis of collagen‐bound VWF attributed the effect to altered binding of VWF to collagen. AFM measurements showed that thiol‐blockade reduced the lifetime and strength of the VWF‐collagen bond. Pulling simulations of the VWF‐C4 domain demonstrated that with one or two reduced disulphide bonds the C4 domain has increased flexibility and the propensity to undergo free‐thiol exchange.ConclusionsWe conclude that free thiols in the C‐domains of VWF enhance the flexibility of the molecule and enable it to withstand high shear forces following collagen binding, demonstrating a previously unrecognized role for VWF free thiols.

Journal article

Boi L, Pisanu A, Fusco G, Carboni E, Casu MA, Satta V, Scherma M, Janda E, Palmas MF, Mocci I, Ena A, Mulas G, Spiga S, Fadda P, De Simone A, Carta Aet al., 2020, Modeling Parkinson’s disease neuropathology and symptoms by intranigral inoculation of preformed human α-synuclein oligomers, International Journal of Molecular Sciences, Vol: 21, ISSN: 1422-0067

The accumulation of aggregated α-synuclein (αSyn) is a hallmark of Parkinson’s disease (PD). Current evidence indicates that small soluble αSyn oligomers (αSynOs) are the most toxic species among the forms of αSyn aggregates, and that size and topological structural properties are crucial factors for αSynOs-mediated toxicity, involving the interaction with either neurons or glial cells. We previously characterized a human αSynO (H-αSynO) with specific structural properties promoting toxicity against neuronal membranes. Here, we tested the neurotoxic potential of these H-αSynOs in vivo, in relation to the neuropathological and symptomatic features of PD. The H-αSynOs were unilaterally infused into the rat substantia nigra pars compacta (SNpc). Phosphorylated αSyn (p129-αSyn), reactive microglia, and cytokine levels were measured at progressive time points. Additionally, a phagocytosis assay in vitro was performed after microglia pre-exposure to αsynOs. Dopaminergic loss, motor, and cognitive performances were assessed. H-αSynOs triggered p129-αSyn deposition in SNpc neurons and microglia and spread to the striatum. Early and persistent neuroinflammatory responses were induced in the SNpc. In vitro, H-αSynOs inhibited the phagocytic function of microglia. H-αsynOs-infused rats displayed early mitochondrial loss and abnormalities in SNpc neurons, followed by a gradual nigrostriatal dopaminergic loss, associated with motor and cognitive impairment. The intracerebral inoculation of structurally characterized H-αSynOs provides a model of progressive PD neuropathology in rats, which will be helpful for testing neuroprotective therapies.

Journal article

Heller GT, Aprile FA, Michaels TCT, Limbocker R, Perni M, Ruggeri FS, Mannini B, Lohr T, Bonomi M, Camilloni C, De Simone A, Felli IC, Pierattelli R, Knowles TPJ, Dobson CM, Vendruscolo Met al., 2020, Small-molecule sequestration of amyloid-β as a drug discovery strategy for Alzheimer's disease, SCIENCE ADVANCES, Vol: 6, ISSN: 2375-2548

Journal article

Stephens AD, Zacharopoulou M, Moons R, Fusco G, Seetaloo N, Chiki A, Woodhams PJ, Mela I, Lashuel HA, Phillips JJ, De Simone A, Sobott F, Schierle GSKet al., 2020, Extent of N-terminus exposure of monomeric alpha-synuclein determines its aggregation propensity, NATURE COMMUNICATIONS, Vol: 11, ISSN: 2041-1723

Journal article

Navarro-Paya C, Sanz-Hernandez M, De Simone A, 2020, In Silico Study of the Mechanism of Binding of the N-Terminal Region of α Synuclein to Synaptic-Like Membranes, LIFE-BASEL, Vol: 10

Journal article

Carta AR, Boi L, Pisanu A, Palmas MF, Carboni E, De Simone Aet al., 2020, Advances in modelling alpha-synuclein-induced Parkinson's diseases in rodents: Virus-based models versus inoculation of exogenous preformed toxic species, JOURNAL OF NEUROSCIENCE METHODS, Vol: 338, ISSN: 0165-0270

Journal article

Visconti L, Toto A, Jarvis J, Troilo F, Malagrino F, De Simone A, Gianni Set al., 2020, Demonstration of binding induced structural plasticity in a SH2 domain, Frontiers in Molecular Biosciences, Vol: 7, ISSN: 2296-889X

SH2 domains are common protein interaction domains able to recognize short aminoacidic sequences presenting a phosphorylated tyrosine (pY). In spite of their fundamental importance for cell physiology there is a lack of information about the mechanism by which these domains recognize and bind their natural ligands. The N-terminal SH2 (N-SH2) domain of PI3K mediates the interaction with different scaffolding proteins and is known to recognize a specific pY-X-X-M consensus sequence. These interactions are at the cross roads of different molecular pathways and play a key role for cell development and division. By combining mutagenesis, chemical kinetics and NMR, here we provide a complete characterization of the interaction between N-SH2 and a peptide mimicking the scaffolding protein Gab2. Our results highlight that N-SH2 is characterized by a remarkable structural plasticity, with the binding reaction being mediated by a diffused structural region and not solely by the residues located in the binding pocket. Furthermore, the analysis of kinetic data allow us to pinpoint an allosteric network involving residues far from the binding pocket involved in specificity. Results are discussed on the light of previous works on the binding properties of SH2 domains.

Journal article

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