Article
Neurosciences
Antonio Dominguez-Meijide, Valeria Parrales, Eftychia Vasili, Florencia Gonzalez-Lizarraga, Annekatrin Konig, Diana F. Lazaro, Annie Lannuzel, Stephane Haik, Elaine Del Bel, Rosana Chehin, Rita Raisman-Vozari, Patrick P. Michel, Nicolas Bizat, Tiago Fleming Outeiro
Summary: Doxycycline shows neuroprotective effects by reducing and inhibiting the aggregation of α-synuclein, attenuating oxidative stress in cells, and may be an effective strategy against synucleinopathies such as Parkinson's disease.
NEUROBIOLOGY OF DISEASE
(2021)
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.
Article
Neurosciences
Yoshitsugu Nakamura, Shigeki Arawaka, Hiroyasu Sato, Asuka Sasaki, Taro Shigekiyo, Kazue Takahata, Hiroko Tsunekawa, Takeo Kato
Summary: Inhibiting MAO-B enzymatic activity can facilitate the secretion of alpha-synuclein and delay protein aggregation and loss of dopaminergic neurons in Parkinson's disease models.
JOURNAL OF NEUROSCIENCE
(2021)
Article
Biochemistry & Molecular Biology
Emma Lorentzon, Istvan Horvath, Ranjeet Kumar, Joana Isabel Rodrigues, Markus J. Tamas, Pernilla Wittung-Stafshede
Summary: Exposure to arsenic and cadmium alters alpha-synuclein amyloid fiber structures and distribution within yeast cells, reducing aggregate clearance and aggravating toxicity. In vitro studies suggest interactions between these heavy metals and alpha-synuclein may modulate the pathogenesis of Parkinson's disease.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
R. Kavya, Snehal Aouti, Sneha Jos, Thazhe Kootteri Prasad, K. N. Kumuda, Sruthi Unni, Balasundaram Padmanabhan, Neelagandan Kamariah, Sivaraman Padavattan, Rajeswara Babu Mythri
Summary: Alpha-synuclein aggregation, associated with Parkinson's disease, is driven by the region alpha Syn(36-42) and alpha Syn(1-12). Celastrol, one of the screened phytochemicals, exhibits high binding affinity with alpha Syn. NMR analysis confirms stable interactions between alpha Syn and celastrol, reducing alpha Syn aggregation, making celastrol a potential drug candidate for Parkinson's disease.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Biochemistry & Molecular Biology
Animesh Mondal, Sandip Dolui, Sukhamoy Dhabal, Shubham Kundu, Lopamudra Das, Ashish Bhattacharjee, Nakul C. Maiti
Summary: Parkinson's disease is associated with the aggregation of α-synuclein and the accumulation of amyloid in the substantia nigra region of the brain. This study identified two types of α-synuclein oligomers with different protein conformation and stability, and compared their toxic effects on neuronal cells. The lyophilized oligomer was highly toxic, while the heat-induced oligomer was less toxic. It was also found that the presence of molten globule-like conformation in the oligomer increased its toxicity to cultured neuronal cells.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2023)
Article
Biochemistry & Molecular Biology
Anne K. Braczynski, Marc Sevenich, Ian Gering, Tatsiana Kupreichyk, Emil D. Agerschou, Yannick Kronimus, Pardes Habib, Matthias Stoldt, Dieter Willbold, Jorg B. Schulz, Jan-Philipp Bach, Bjorn H. Falkenburger, Wolfgang Hoyer
Summary: Parkinson's disease is associated with changes in the abundance of naturally occurring antibodies (nAbs) against alpha-synuclein (α Syn). In this study, nAbs-alpha Syn were found to specifically bind monomeric α Syn and inhibit its aggregation in vitro. Additionally, the addition of nAbs-alpha Syn to cultured cells affected intracellular α Syn aggregates.
Article
Medicine, Research & Experimental
Sinyeon Kim, Jin Gyu Choi, Se Woong Kim, Sang Cheol Park, Yu-ra Kang, Dong Seok Park, Miwon Son, Choong Hwan Lee
Summary: The herbal formula MT101-5 has been found to have neuroprotective effects against alpha-synuclein-induced cytotoxicity, improving behavioral deficits and loss of dopaminergic neurons in a mouse model of Parkinson's disease. It is believed that MT101-5 achieves this through changes in mitochondrial biogenesis, electron transport, chaperones, and proteasomes. These findings suggest that MT101-5 could be a potential pharmaceutical agent for preventing or improving Parkinson's disease.
BIOMEDICINE & PHARMACOTHERAPY
(2022)
Article
Biochemistry & Molecular Biology
Gabriel Bernardes, Omer Munir, Ed S. Krol
Summary: The naturally-occurring di-catechol lignan nordihydroguaiaretic acid (NDGA) and its analog both undergo intramolecular cyclization to form dibenzocyclooctadienes. These compounds have been shown to prevent the aggregation of alpha-synuclein, a protein associated with Parkinson's disease. The presence of vicinal methyl groups on NDGA's butyl linker attenuates the rate of cyclization, likely due to steric repulsions during cyclization. Moreover, a series of 1,2-bis-ethane di-catechols with methyl substituents have been found to undergo intramolecular cyclization to form dibenzocyclohexadienes, and the rate of cyclization is increased with the presence of methyl groups.
BIOORGANIC & MEDICINAL CHEMISTRY
(2023)
Article
Agriculture, Multidisciplinary
Wenqian Wang, Lili Qu, Zhan Cui, Fuping Lu, Li Li, Fufeng Liu
Summary: This study shows that the citrus flavonoid hesperetin (Hst) can inhibit the fibrillation of alpha-synuclein (alpha SN) and reduce its cytotoxicity, potentially serving as a dietary supplement to prevent the development of Parkinson's disease (PD).
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
(2023)
Article
Clinical Neurology
Tobias Thom, Matthias Schmitz, Anna-Lisa Fischer, Angela Correia, Susana Correia, Franc Llorens, Anna-Villar Pique, Wiebke Moebius, Renato Domingues, Saima Zafar, Erik Stoops, Christopher J. Silva, Andre Fischer, Tiago F. Outeiro, Inga Zerr
Summary: Expressing PrPC in mice led to behavioral deficits and increased levels of aSyn oligomers; PrPC colocalized with aSyn and facilitated its internalization in cell models; Clathrin was identified to regulate aSyn internalization by binding to recombinant PrP.
MOVEMENT DISORDERS
(2022)
Review
Biochemistry & Molecular Biology
Panagiota Mavroeidi, Maria Xilouri
Summary: The abnormal accumulation of alpha-synuclein in both neurons and glial cells plays a key role in the pathogenesis of a-synucleinopathies. This aggregation can disrupt normal glial cell function and contribute to neurodegeneration through various pathways, making it a potential therapeutic target for these disorders.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
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)
Review
Biochemistry & Molecular Biology
Ryan Limbocker, Silvia Errico, Denise Barbut, Tuomas P. J. Knowles, Michele Vendruscolo, Fabrizio Chiti, Michael Zasloff
Summary: Alzheimer's and Parkinson's diseases, affecting over 50 million people worldwide, are still largely intractable pharmacologically. Research suggests that natural products squalamine and trodusquemine offer promising opportunities for chronic treatments by preventing the formation of neurotoxic oligomers and their interaction with cell membranes.
NATURAL PRODUCT REPORTS
(2022)
Review
Pharmacology & Pharmacy
Md Ezazul Haque, Mahbuba Akther, Shofiul Azam, In-Su Kim, Yuxi Lin, Young-Ho Lee, Dong-Kug Choi
Summary: In Parkinson's disease, the aggregated alpha-synuclein in Lewy bodies and mitochondrial dysfunction play crucial roles in neurodegeneration, with interactions between aggregated alpha-synuclein and mitochondria potentially leading to neuronal loss, making it an emerging drug target for Parkinson's disease treatment.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Medicine, General & Internal
Roberta Cascella, Martina Banchelli, Seyyed Abolghasem Ghadami, Diletta Ami, Maria Cristina Gagliani, Alessandra Bigi, Tommaso Staderini, Davide Tampellini, Katia Cortese, Cristina Cecchi, Antonino Natalello, Hadi Adibi, Paolo Matteini, Fabrizio Chiti
Summary: This study investigated the morphological, structural, and tinctorial properties of TAR DNA-binding protein 43 (TDP-43) inclusions in neuroblastoma x spinal cord 34 (NSC-34) cells. The results showed that TDP-43 inclusions did not exhibit amyloid properties and lacked cross-beta structure and fibrillar morphology. These findings suggest that TDP-43 has a low propensity to form amyloid fibrils and instead forms other types of inclusions.
ANNALS OF MEDICINE
(2023)
Article
Biochemical Research Methods
Marc Oeller, Ryan Kang, Rosie Bell, Hannes Ausserwoger, Pietro Sormanni, Michele Vendruscolo
Summary: This article describes a computational method that incorporates the effect of pH on protein solubility predictions. The accuracy of these predictions is comparable to experimental methods, as demonstrated on various antibodies and proteins. This method, named CamSol 3.0, is now publicly available at https://www-cohsoftware.ch.cam.ac.uk/index.php/camsolph.
BRIEFINGS IN BIOINFORMATICS
(2023)
Review
Chemistry, Multidisciplinary
Ryan Limbocker, Nunilo Cremades, Roberta Cascella, Peter M. Tessier, Michele Vendruscolo, Fabrizio Chiti
Summary: The misfolding and aggregation of peptides and proteins into amyloid aggregates is a common feature of various protein misfolding diseases, including Alzheimer's disease and Parkinson's disease. Misfolded protein oligomers, which can form intermediates in the fibril formation process or be released by mature fibrils, are increasingly recognized as central to the development of these diseases. Despite challenges in studying these oligomers, researchers have developed methods to produce stable and reproducible populations for experimentation. These tools have provided insights into the structural determinants of oligomer toxicity and potential therapeutic strategies.
ACCOUNTS OF CHEMICAL RESEARCH
(2023)
Article
Nanoscience & Nanotechnology
Zenon Toprakcioglu, Elizabeth G. Wiita, Akhila K. Jayaram, Rebecca C. Gregory, Tuomas P. J. Knowles
Summary: The emergence of drug-resistant bacteria and fungi is a global concern in healthcare. Developing effective small molecule therapeutic strategies is challenging, thus, exploring biomaterials with physical modes of action is an alternative approach. In this study, silk-based films embedded with selenium nanoparticles were found to exhibit antibacterial and antifungal properties while remaining biocompatible and noncytotoxic towards mammalian cells.
ACS APPLIED MATERIALS & INTERFACES
(2023)
Article
Chemistry, Multidisciplinary
Qi Zhang, Zenon Toprakcioglu, Akhila K. Jayaram, Guangsheng Guo, Xiayan Wang, Tuomas P. J. Knowles
Summary: Nanoparticles have become increasingly important in biological applications, but obtaining stable and controlled protein nanoparticles has been challenging. In this study, we used droplet microfluidics to produce highly monodisperse protein nanoparticles by utilizing the characteristic of rapid and continuous mixing in microdroplets. The internal vortex flows within microdroplets were found to determine the uniformity of the nanoparticles, and by adjusting parameters such as protein concentration and flow rates, we were able to control the nanoparticle size. These protein nanoparticles showed high biocompatibility with HEK-293 cells and were able to fully enter the cells. Due to the high throughput and level of control, this approach has the potential for future intracellular drug delivery or gene transfection.
Article
Biophysics
Matthias M. Schneider, Tom Scheidt, Ashley J. Priddey, Catherine K. Xu, Mengsha Hu, Georg Meisl, Sean R. A. Devenish, Christopher M. Dobson, Vasilis Kosmoliaptsis, Tuomas P. J. Knowles
Summary: Antibody profiling is essential in understanding humoral response in various diseases. By using microfluidic diffusional sizing (MDS), we successfully quantified the binding affinity and concentration of alloantibodies to HLA proteins, a widely used clinical biomarker in organ transplantation, in both buffer and crude human serum. Our assay offers a potential path for in-depth profiling of humoral immunity and further insights into the clinical relevance of antibody reactivity.
BIOSENSORS & BIOELECTRONICS
(2023)
Review
Pharmacology & Pharmacy
Michele Vendruscolo
Summary: Protein misfolding diseases, such as Alzheimer's and Parkinson's diseases, have a major impact on our healthcare systems and societies. This paper discusses drug discovery strategies to target protein misfolding and aggregation, including thermodynamic and kinetic approaches. There is a need for disease-modifying treatments to address the over 50 human disorders associated with protein misfolding and aggregation.
EXPERT OPINION ON DRUG DISCOVERY
(2023)
Editorial Material
Biochemistry & Molecular Biology
Alessandra Bigi, Eva Lombardo, Roberta Cascella, Cristina Cecchi
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Clinical Neurology
Mark R. Wilson, Sandeep Satapathy, Michele Vendruscolo
Summary: The proteostasis system regulates cellular processes of protein synthesis, folding, concentration, trafficking, and degradation. The mechanisms of extracellular proteostasis, particularly in the context of neurodegenerative diseases, are not well understood, but growing evidence suggests that impairment of this system may contribute to neuronal death.
NATURE REVIEWS NEUROLOGY
(2023)
Article
Biochemistry & Molecular Biology
Andras Hatos, Joao M. C. Teixeira, Susana Barrera-Vilarmau, Attila Horvath, Silvio C. E. Tosatto, Michele Vendruscolo, Monika Fuxreiter
Summary: Proteins form complex interactions in the cellular environment. The FuzPred server predicts their binding modes based on sequence without specifying the binding partners. The server also estimates the multiplicity of binding modes and visualizes different interaction behaviors on protein structures.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Multidisciplinary Sciences
Alyssa Miller, Jiapeng Wei, Sarah Meehan, Christopher M. Dobson, Mark E. Welland, David Klenerman, Michele Vendruscolo, Francesco Simone Ruggeri, Tuomas P. J. Knowles
Summary: Neurodegenerative diseases such as Alzheimer's disease are caused by protein misfolding and aggregation into amyloid fibrils. This study uses atomic force microscopy and statistical theory to characterize amyloid ring structures derived from the brains of AD patients and explains the diversity in the structures formed from protein aggregation. The results show that ex vivo protofibril chains possess greater flexibility than mature amyloid fibrils, allowing them to form end-to-end connections and shedding light on their role in disease.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Biology
Esther Stroo, Leen Janssen, Olga Sin, Wytse Hogewerf, Mirjam Koster, Liesbeth Harkema, Sameh A. Youssef, Natalie Beschorner, Anouk H. G. Wolters, Bjorn Bakker, Lore Becker, Lilian Garrett, Susan Marschall, Sabine M. Hoelter, Wolfgang Wurst, Helmut Fuchs, Valerie Gailus-Durner, Martin Hrabe de Angelis, Amanth Thathiah, Floris Foijer, Bart van de Sluis, Jan van Deursen, Matthias Jucker, Alain de Brun, Ellen A. A. Nollen
Summary: In age-related neurodegenerative diseases, disease-specific proteins form amyloid-like deposits. Depletion of SERF proteins can ameliorate this process. However, it is unknown whether SERF modifies amyloid pathology in mammalian brain.
LIFE SCIENCE ALLIANCE
(2023)
Article
Biochemistry & Molecular Biology
Z. Faidon Brotzakis, Thomas Lohr, Steven Truong, Samuel Hoff, Massimiliano Bonomi, Michele Vendruscolo
Summary: In recent years, cryo-electron microscopy has made significant advancements in determining biomolecular structures at the atomic level. However, studying large systems with continuous dynamics using this method has been a challenge. To address this, the metadynamic electron microscopy metainference (MEMMI) method was developed, which combines cryo-EM density maps with prior information to determine the structure and dynamics of large heterogeneous systems. This method was applied to study the amyloid fibril dynamics of the islet amyloid polypeptide (IAPP), revealing interesting characteristics of the fibril's structural variability and liquid-like dynamics in the core region.
Article
Biochemistry & Molecular Biology
Chenrong Yu, Spencer L. Nelson, Georg Meisl, Rodolfo Ghirlando, Lalit Deshmukh
Summary: Human annexin A7 has been found to form fibrils through its N-terminal proline-rich domain and the fibrillation mechanism has been elucidated, providing new insights into the amyloid assembly of this protein. This discovery is of significant importance for understanding the physiological and pathological functions of this protein.
Article
Chemistry, Medicinal
Silvia Errico, Giacomo Lucchesi, Davide Odino, Enass Youssef Osman, Roberta Cascella, Lorenzo Neri, Claudia Capitini, Martino Calamai, Francesco Bemporad, Cristina Cecchi, William A. Kinney, Denise Barbut, Annalisa Relini, Claudio Canale, Gabriella Caminati, Ryan Limbocker, Michele Vendruscolo, Michael Zasloff, Fabrizio Chiti
Summary: Natural aminosterols are potential drugs for treating neurodegenerative diseases, and their protective mechanism involves binding to biological membranes and inhibiting amyloidogenic proteins. Three chemically different aminosterols were compared and found to have different binding affinities, charge neutralizations, mechanical reinforcements, and lipid redistributions within liposomes. They also exhibited varying potency in protecting cell membranes against amyloid-beta oligomers. Overall analysis provided an analytical equation that quantitatively described the protective effects of aminosterols based on their concentration and membrane effects, linking their chemistry to membrane protection.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)