Article
Multidisciplinary Sciences
Pratibha Kumari, Dhiman Ghosh, Agathe Vanas, Yanick Fleischmann, Thomas Wiegand, Gunnar Jeschke, Roland Riek, Cedric Eichmann
Summary: This study investigated the interaction between monomeric alpha-Syn and its fibrillar form using NMR and electron paramagnetic resonance spectroscopy, revealing that intermolecular interactions reduce intramolecular contacts in monomeric alpha-Syn, leading to further unfolding of its intrinsically disordered states and critically contributing to the aggregation kinetics of alpha-Syn during secondary nucleation.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Biochemistry & Molecular Biology
Gobert Heesink, Mirjam J. Marseille, Mohammad A. A. Fakhree, Mark D. Driver, Kirsten A. van Leijenhorst-Groener, Patrick R. Onck, Christian Blum, Mireille M. A. E. Claessens
Summary: Theoretical concepts from polymer physics are frequently used to describe the behavior of intrinsically disordered proteins (IDPs). However, interactions between amino acids within the protein can lead to deviations from typical polymer scaling behavior and the emergence of short-lived secondary structures. In this study, we investigated the interactions in the highly dynamic IDP α-synuclein at the amino acid level using single-molecule fluorescence resonance energy transfer experiments and molecular dynamics simulations. Our results demonstrate excellent agreement between experiments and simulations, revealing the effects of intra- and inter-regional interactions on the folding and conformation of α-synuclein. Overall, this study highlights the importance of combining experimental and computational approaches to understand the key interactions in highly dynamic IDPs.
Article
Chemistry, Multidisciplinary
Mario Gonzalez-Garcia, Giuliana Fusco, Alfonso De Simone
Summary: This study investigated the conformational changes of α-synuclein (aS) upon binding with metal ions using nuclear magnetic resonance (NMR). It was found that binding to calcium and zinc reduced the protection factors in the C-terminal region of the protein, while binding to copper did not affect the amide proton exchange. N-15 relaxation experiments showed conformational perturbations in distinctive regions of the protein upon binding with Cu+ and Zn2+. Overall, these results suggest multiple mechanisms contribute to enhanced aS aggregation through metal binding.
FRONTIERS IN CHEMISTRY
(2023)
Review
Biochemistry & Molecular Biology
Jennifer Ramirez, Samantha X. Pancoe, Elizabeth Rhoades, E. James Petersson
Summary: This article investigates the effects of interactions between the small neuronal protein alpha-synuclein and lipids on aggregation. By analyzing a comprehensive collection of experimental data, the general trends of lipid structure influencing aggregation are identified, providing a resource for interpreting the effects of lipids on aggregation and potentially serving as inputs for computational models.
Review
Biochemistry & Molecular Biology
Greta Musteikyte, Akhila K. Jayaram, Catherine K. Xu, Michele Vendruscolo, Georg Krainer, Tuomas P. J. Knowles
Summary: Parkinson's disease is an incurable neurodegenerative disorder characterized by the formation of Lewy bodies. Oligomeric forms of the protein alpha-synuclein interacting with lipid membranes are considered the main pathogenic species. Understanding the structural and biophysical features of these oligomers and their interactions with membranes is crucial for deciphering the etiology of Parkinson's disease and its toxicity in vivo.
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
(2021)
Review
Chemistry, Multidisciplinary
Upneet Kaur, Jennifer C. Lee
Summary: The research highlights the importance of alpha-synuclein's interactions with cellular membranes for its physiological and pathological functions, revealing the effects of the chemical nature of phospholipid headgroups on the interplay among membrane remodeling, protein structure, and alpha-syn amyloid formation.
ACCOUNTS OF CHEMICAL RESEARCH
(2021)
Article
Medicine, General & Internal
Angelo M. Jamerlan, Seong Soo A. An
Summary: In this study, the interaction between TDP-43 and alpha-synuclein was investigated using a solid-phase microplate-based immunoassay. The results showed that a region of the low complexity domain of TDP-43 interacts with full-length alpha-synuclein. This method provides a convenient, economical, and rapid way to locate antibody epitopes and interaction sites of two proteins.
JOURNAL OF CLINICAL MEDICINE
(2022)
Article
Biochemistry & Molecular Biology
Anshuman Mohapatra, Nitin Chaudhary
Summary: The study compared the interfacial properties of N-terminal acetylated alpha S with non-acetylated alpha S at the air-water interface, showing both protein forms to be highly surface-active and exhibit large hysteresis in pressure-area isotherms, indicating self-assembly at higher surface pressures. The expansion isotherm revealed a rapid decrease in surface pressure followed by a slower transition phase, suggesting the compressed monolayer breaks into small clusters upon expansion. The circular dichroism analysis indicated the protein to be largely in alpha-helical conformation, and linear dichroism investigations suggested anisotropic deposition of the protein.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2021)
Article
Chemistry, Multidisciplinary
Muhammad Ayaz Anwar, Muhammad Haseeb, Sangdun Choi, Kwang Pyo Kim
Summary: Maspin is a protein that regresses tumors by inhibiting angiogenesis, but its effects depend on the context and sequence. Various proteins and cofactors bind to maspin, which may explain its conflicting roles. Polymorphic forms of maspin have also been linked to tumor regression and survival, with different amino acids at position 176 having opposing effects in cancer development. Molecular dynamics simulations have revealed a possible link between polymorphic forms and tumor progression, showing that altered electrostatics affect the localization and preference of maspin-binding partners, leading to different maspin-protein(companion)-interaction landscapes.
Article
Chemistry, Multidisciplinary
Hossein Mohammad-Beigi, Masumeh Zanganeh, Carsten Scavenius, Hoda Eskandari, Azad Farzadfard, Seyed Abbas Shojaosadati, Jan J. Enghild, Daniel E. Otzen, Alexander K. Buell, Duncan S. Sutherland
Summary: Nanoparticles can modulate protein aggregation and fibril formation in amyloid diseases. By attaching a protein corona to the nanoparticles, the interactions between alpha-Synuclein and the nanoparticles were studied. The results showed that the nanoparticles surface promotes the primary nucleation step of fibril formation and that the protein corona reduces the accelerating effect of the nanoparticles.
Article
Multidisciplinary Sciences
Sabine M. Ulamec, Roberto Maya-Martinez, Emily J. Byrd, Katherine M. Dewison, Yong Xu, Leon F. Willis, Frank Sobott, George R. Heath, Patricija van Oosten Hawle, Vladimir L. Buchman, Sheena E. Radford, David J. Brockwell
Summary: In this study, the authors characterized the impact of amino acid substitution on alpha-synuclein aggregation. They found that residues 38 and 42 within the P1 region of alpha-synuclein influence amyloid formation.
NATURE COMMUNICATIONS
(2022)
Article
Chemistry, Multidisciplinary
Arun Kumar Somavarapu, Giulia Kleijwegt, Madhu Nagaraj, Parvez Alam, Janni Nielsen, Daniel E. Otzen
Summary: Small soluble oligomers of the protein alpha-synuclein (alpha SO) have been identified as contributing factors to Parkinson's Disease (PD) through disruptions in neuronal homeostasis. However, the development of effective therapeutics against alpha SO is challenging due to its low abundance and complex structure. This study employed two different approaches to neutralize the toxic interactions of alpha SO, identifying potential interaction candidates and screening disruptors of these interactions using vesicles consisting of anionic lipids. The results showed promise in impairing alpha SO contacts with other proteins and suppressing alpha-synuclein amyloid formation.
Article
Biochemistry & Molecular Biology
Dorothy Das, Priyam Bharadwaz, Venkata Satish Kumar Mattaparthi
Summary: This study investigated the effect of peptidomimetic inhibitors on the interaction between alpha-Syn and cell membranes. The inhibitors were found to stabilize the structure of alpha-Syn and bind closely to lipid membranes. These findings may have important implications for the development of new therapeutic approaches for Parkinson's disease and other neurodegenerative disorders.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Review
Biochemistry & Molecular Biology
Abbie T. Rodger, Maryam A. L. Nasser, Wayne G. Carter
Summary: Currently, there are no pharmacological treatments that can completely stop or reverse the progression of Parkinson's Disease (PD). Therefore, there is a need for neuroprotective therapies. This systematic review examines the effectiveness of anti-a-synuclein (a-syn) therapies in preventing PD progression in preclinical models and human clinical trials. The review found that novel preclinical anti-a-syn therapeutics reduced a-syn aggregations and protected against dopaminergic neuronal loss. Completed clinical trials showed significant tolerability and efficacy in reducing a-syn and minimal adverse effects. Overall, this review highlights the potential of anti-a-syn therapies in both preclinical and clinical settings to reduce a-syn accumulation and potentially slow down PD progression.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Multidisciplinary Sciences
Dmitry Zenko, Jade Marsh, Andrew R. Castle, Rahel Lewin, Roman Fischer, George K. Tofaris
Summary: We developed a bimolecular fluorescence complementation assay to monitor de novo ubiquitination of alpha-synuclein, and identified lysine residues 45, 58, and 60 as critical sites for its degradation. The degradation involves NBR1 binding, entry into endosomes and subsequent lysosomal degradation. Our data also show the presence of ubiquitinated alpha-synuclein in Lewy bodies and cellular models of aggregation.
Review
Biochemistry & Molecular Biology
Kalkena Sivanesam, Niels Andersen
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
(2019)
Article
Chemistry, Multidisciplinary
Francesca Munari, Carlo G. Barracchia, Cinzia Franchin, Francesca Parolini, Stefano Capaldi, Alessandro Romeo, Luigi Bubacco, Michael Assfalg, Giorgio Arrigoni, Mariapina D'Onofrio
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2020)
Review
Biochemistry & Molecular Biology
Marco Bisaglia, Luigi Bubacco
Article
Biochemistry & Molecular Biology
Francesca Munari, Carlo Giorgio Barracchia, Francesca Parolini, Roberto Tira, Luigi Bubacco, Michael Assfalg, Mariapina D'Onofrio
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2020)
Article
Biochemistry & Molecular Biology
Carlo Giorgio Barracchia, Roberto Tira, Francesca Parolini, Francesca Munari, Luigi Bubacco, Georgios A. Spyroulias, Mariapina D'Onofrio, Michael Assfalg
Article
Neurosciences
Alice Filippini, Veronica Mutti, Gaia Faustini, Francesca Longhena, Ileana Ramazzina, Federica Rizzi, Alice Kaganovich, Dorien A. Roosen, Natalie Landeck, Megan Duffy, Isabella Tessari, Federica Bono, Chiara Fiorentini, Elisa Greggio, Luigi Bubacco, Arianna Bellucci, Mariacristina Missale, Mark R. Cookson, Massimo Gennarelli, Isabella Russo
Summary: The progressive neuropathological damage in Parkinson's disease is believed to be related to the spread of aggregated forms of alpha-synuclein. Clearance of extracellular alpha-synuclein by neurons may be a key mechanism to control its concentration. Clusterin, a glycoprotein associated with Alzheimer's disease, interacts with alpha-synuclein aggregates and limits their uptake by astrocytes, which may contribute to the spreading of Parkinson's pathology.
Article
Chemistry, Medicinal
Paolo Moretti, Paolo Mariani, Maria Grazia Ortore, Nicoletta Plotegher, Luigi Bubacco, Mariano Beltramini, Francesco Spinozzi
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2020)
Article
Neurosciences
David Sulzer, Angelo Antonini, Valentina Leta, Anna Nordvig, Richard J. Smeyne, James E. Goldman, Osama Al-Dalahmah, Luigi Zecca, Alessandro Sette, Luigi Bubacco, Olimpia Meucci, Elena Moro, Ashley S. Harms, Yaqian Xu, Stanley Fahn, K. Ray Chaudhuri
NPJ PARKINSONS DISEASE
(2020)
Article
Chemistry, Multidisciplinary
Giulia Marafon, Marco Crisma, Anna Masato, Nicoletta Plotegher, Luigi Bubacco, Alessandro Moretto
Summary: Proteins undergo changes in their 3D structure and function through specific molecular interactions, which is crucial for sensing, processing, and transmitting information from the surrounding environment. The study of early aggregation steps of alpha-synuclein associated with Parkinson's disease showed that light-mediated binding with a photoactive foldamer can promote the process by generating supramolecular fibrillar seeds that act as molecular templates for inducing fast beta-sheet transitions in monomers. This proposed method provides a powerful tool for studying protein aggregation in misfolding diseases in a controlled and inducible system.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Chemistry, Multidisciplinary
Elina Buitrago, Clarisse Faure, Lylia Challali, Elisabetta Bergantino, Ahcene Boumendjel, Luigi Bubacco, Marcello Carotti, Renaud Hardre, Marc Maresca, Christian Philouze, Helene Jamet, Marius Reglier, Catherine Belle
Summary: In this study, a combination of known inhibitors targeting the binuclear copper active site on tyrosinases was investigated, revealing significant enhancement of inhibitory effects, particularly for the HOPNO-TSC compound. The interaction mode with the dicopper(II) active site was elucidated through binding studies with a tyrosinase bio-inspired model, showing that binding to the dicopper center can occur with both chelating sites. Computational and docking studies identified the kojic acid and HOPNO moieties as interacting groups with the dicopper active site.
CHEMISTRY-A EUROPEAN JOURNAL
(2021)
Review
Biochemistry & Molecular Biology
Francesco Agostini, Anna Masato, Luigi Bubacco, Marco Bisaglia
Summary: This article reviews the potential mechanisms and clinical applications of metformin in the treatment of Parkinson's disease. Studies have shown that metformin may exert neuroprotective effects by regulating cellular pathways such as autophagy, degradation of pathological proteins, and mitochondrial function. Epidemiological studies on the correlation between long-term metformin use and the risk of developing Parkinson's disease are also discussed. However, there is controversy regarding the results obtained from experimental models and clinical studies, and further research is needed to clarify the mechanisms and efficacy of metformin in the treatment of Parkinson's disease.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Neurosciences
Adrianne F. Pike, Ildiko Szabo, Robert Veerhuis, Luigi Bubacco
Summary: This review suggests a hypothesis that Kv1.3 activity-induced NLRP3 inflammasome activation in microglia may be counteracted by the utilization of dopamine from adjacent dopaminergic neurons, preventing microglial activation. However, as dopamine supply decreases, NLRP3 inflammasome activation and Kv1.3 activity would intensify, leading to the development of the major pathological features of Parkinson's disease.
NPJ PARKINSONS DISEASE
(2022)
Article
Chemistry, Multidisciplinary
Andrea Capucciati, Enrico Monzani, Michela Sturini, Stefania Nicolis, Fabio A. Zucca, Luigi Bubacco, Marco Bortolus, Luigi Zecca, Luigi Casella
Summary: The study uses water-soluble melanin-protein-Fe/Cu conjugates derived from norepinephrine and fibrillar beta-lactoglobulin as reliable models for human brain locus coeruleus neuromelanin (NM). Iron and copper promote catecholamine oxidation and tend to remain coupled in oligonuclear aggregates. The Fe-Cu clusters are EPR silent and affect the H-1 NMR spectra of the conjugates.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Biochemistry & Molecular Biology
Federica De Lazzari, Francesco Agostini, Davide Doni, Sandro Malacrida, Mauro A. Zordan, Paola Costantini, Luigi Bubacco, Federica Sandrelli, Marco Bisaglia
Summary: Redox homeostasis plays a vital role in various pathological processes, including neurodegenerative disorders. SOD1 and DJ-1 are key enzymes involved in the antioxidant response, and they play important roles in the maturation process of proteins. Our study demonstrates that the protective activity of DJ-1 in fruit flies is independent of SOD1, suggesting different mechanisms of action.
Article
Biology
Sophia von Stockum, Alvaro Sanchez-Martinez, Samantha Corra, Joy Chakraborty, Elena Marchesan, Lisa Locatello, Caterina Da Re, Paola Cusumano, Federico Caicci, Vanni Ferrari, Rodolfo Costa, Luigi Bubacco, Maria Berica Rasotto, Ildiko Szabo, Alexander J. Whitworth, Luca Scorrano, Elena Ziviani
LIFE SCIENCE ALLIANCE
(2019)