Review
Biochemistry & Molecular Biology
Ivana Sirangelo, Clara Iannuzzi
Summary: The study provides an overview of the molecular effects induced by glycation on the amyloid aggregation process of protein models associated with misfolding diseases. Glycation plays a key role in protein folding, kinetics of amyloid formation, and amyloid cytotoxicity.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Cell Biology
Alessandra Bigi, Roberta Cascella, Cristina Cecchi
Summary: The misfolding and aggregation of a-synuclein is the key feature of synucleinopathies, such as Parkinson's disease and dementia with Lewy bodies. Soluble oligomeric assemblies formed during the early stages of aggregation are toxic to neurons, while fibrillar conformers contribute to the spreading of the pathology. Recent studies have also shown that a-synuclein fibrils release soluble and highly toxic oligomeric species, leading to immediate dysfunction in recipient neurons. This review discusses the mechanisms of cellular dysfunction caused by a-synuclein oligomers and fibrils in synucleinopathies.
NEURAL REGENERATION RESEARCH
(2023)
Article
Neurosciences
Patricia Aguilar-Calvo, Alejandro M. Sevillano, Suhail Rasool, Kevin J. Cao, Lyndsay M. Randolph, Robert A. Rissman, Stella T. Sarraf, Jerry Yang, Christina J. Sigurdson
Summary: The retina can be used to diagnose and monitor neurodegenerative diseases, and live imaging using an amyloid-binding fluorescent probe and high-resolution retinal microscopy can directly monitor the progression of amyloid deposits in the eyes.
JOURNAL OF ALZHEIMERS DISEASE
(2022)
Review
Biochemistry & Molecular Biology
Liisa Lutter, Liam D. Aubrey, Wei-Feng Xue
Summary: Predicting the highly ordered three-dimensional structures of amyloid protein fibrils from their monomeric self-assembly precursors remains a challenging aspect of the classical protein folding problem, due to the polymorphic nature of amyloid assembly. Understanding the diversity and individuality of amyloid structures, as well as the link to biology and disease phenotypes, is essential. Current research focuses on resolving the structural basis and biological consequences of polymorphic amyloid assemblies using various techniques such as cryo-EM, ssNMR, and AFM.
JOURNAL OF MOLECULAR BIOLOGY
(2021)
Article
Biophysics
Victoria T. Reichelderfer, Andres F. Chaparro Sosa, Joel L. Kaar, Daniel K. Schwartz
Summary: The interactions between lipid bilayers and insulin can either stabilize or destabilize the protein, preventing or exacerbating the formation of amyloid fibrils.
COLLOIDS AND SURFACES B-BIOINTERFACES
(2022)
Article
Biochemistry & Molecular Biology
Priyanka Borah, Airy Sanjeev, Venkata Satish Kumar Mattaparthi
Summary: Parkinson's disease is a common progressive neurodegenerative disorder caused by misfolding and aggregation of alpha-synuclein. Recent research shows that Oleuropein aglycone (OleA) stabilizes the monomeric structure of alpha-synuclein, preventing the formation of toxic aggregates and favoring the growth of stable ones, highlighting a potential therapeutic approach.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2021)
Article
Biochemical Research Methods
Takahiro Watanabe-Nakayama, Kenjiro Ono
Summary: The structural dynamics of amyloid protein aggregation process play a role in neurodegenerative diseases. High-speed atomic force microscopy (HS-AFM) is a useful tool to visualize individual aggregate species. Correction of stage drift in HS-AFM images can be done using free software like ImageJ, allowing for easier analysis of structural dynamics.
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)
Review
Biochemistry & Molecular Biology
Jin-Beom Si, Bokyung Kim, Jin Hae Kim
Summary: TTR is a crucial transporter of thyroid hormone and retinol binding protein in human plasma and cerebrospinal fluid, yet it is also known for its amyloidogenic nature leading to various amyloidoses. Research has shown that decreased stability of TTR's native tetrameric conformation is the main cause of these diseases, and recent multidisciplinary investigations have shed light on the mechanistic details of TTR amyloidogenic transformation. Special emphasis has been placed on identifying novel structural features in amyloidogenic species of TTR and discussing the proteolysis-induced fragmentation mechanism that promotes TTR amyloidosis.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Engineering, Chemical
Yanxian Zhang, Yijing Tang, Dong Zhang, Yonglan Liu, Jian He, Yung Chang, Jie Zheng
Summary: The research focuses on the mechanism of amyloid cross-seeding between Aβ and hIAPP and its connection between AD and T2D, explores the role of structural compatibility and sequence similarity of amyloid proteins in cross-seeding, and proposes current challenges and future research directions in this less-studied field.
CHINESE JOURNAL OF CHEMICAL ENGINEERING
(2021)
Article
Neurosciences
Anastasiia A. Stepanchuk, Megan L. Morgan, Jeffrey T. Joseph, Peter K. Stys
Summary: Protein misfolding is a prominent feature of neurodegenerative disorders like Alzheimer's disease. A study investigated the binding affinity of fluorescent amyloid probes BSB and MCAAD to disease-related protein aggregates, and analyzed mouse and human brain samples using these probes and quantitative spectral phasor analysis. The approach revealed heterogeneity of protein aggregates across the samples and detected spectral differences between cognitively normal and AD cases, suggesting widespread proteopathy associated with the disease. This method offers a more sensitive, objective, and quantitative examination of protein misfolding pathology.
ACTA NEUROPATHOLOGICA COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Nilamuni H. de Silva, Suneela Pyreddy, Ewan W. Blanch, Helmut M. Hugel, Subashani Maniam
Summary: A library of Sox-pyrrolizidines was efficiently synthesized through a new method, and Nitro-Sox compounds were found to inhibit HEWL amyloid fibril formation. Further experiments suggested that these compounds could potentially combat amyloid misfolding, indicating their potential for Alzheimer's disease treatment.
BIOORGANIC CHEMISTRY
(2021)
Review
Biochemistry & Molecular Biology
Yijing Tang, Dong Zhang, Xiong Gong, Jie Zheng
Summary: This article primarily discusses and summarizes the mechanistic causes of Alzheimer's disease (AD). Different mechanisms of AD could potentially work together to initiate, trigger, and promote the onset and development of the disease. Some of these mechanisms are also applicable to other amyloid diseases, explaining the pathogenesis and pathology spreading among these diseases.
BIOPHYSICAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Maxime Belondrade, Simon Nicot, Charly Mayran, Lilian Bruyere-Ostells, Florian Almela, Michele A. Di Bari, Etienne Levavasseur, Joel C. Watts, Chantal Fournier-Wirth, Sylvain Lehmann, Stephane Haik, Romolo Nonno, Daisy Bougard
Summary: This study evaluated the amplification of PrPTSE from human sCJD brain samples in different substrates using PMCA, revealing the potential of bank vole PrP substrate in amplifying all sCJD subtypes. In contrast, PMCA in human PrP substrates led to molecular shifts in PrPTSE, with increased permissiveness of V129 PrP substrate to sCJD prion amplification. The combination of PMCA sensitivities and PrPTSE electrophoretic profiles confirmed the classification of 4 distinct major sCJD prion strains. Additionally, the sensitivity required to detect VV2 sCJD prions in cerebrospinal fluid was achieved.
SCIENTIFIC REPORTS
(2021)
Article
Chemistry, Multidisciplinary
Katelyn M. Baumer, Christopher D. Cook, Collin T. Zahler, Alexandra A. Beard, Zhijuan Chen, Jordan C. Koone, Chad M. Dashnaw, Raul A. Villacob, Touradj Solouki, John L. Wood, David R. Borchelt, Bryan F. Shaw
Summary: Repulsive electrostatic forces between prion-like proteins hinder aggregation, but compounds selectively boosting the negative charge of misfolded SOD1 were synthesized. These compounds showed slower aggregation of acetylated amyloid-SOD1 compared to unacetylated forms, and exhibited reactivity with other types of proteins.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Review
Clinical Neurology
Carolina Alquezar, Shruti Arya, Aimee W. Kao
Summary: Post-translational modifications play a crucial role in regulating tau protein function, including phosphorylation and acetylation. While these modifications may regulate protein function under normal conditions, they can be hijacked in disease states. Limited understanding exists on how these modifications impact tau protein, but studies indicate their critical role in localization, interactions, and other aspects.
FRONTIERS IN NEUROLOGY
(2021)
Article
Chemistry, Physical
Swapnil Singh, Aishwarya Agarwal, Anamika Avni, Samrat Mukhopadhyay
Summary: The study demonstrates that electrostatic tethering between surface-modified negatively charged silver nanoparticles and highly positively charged intrinsically disordered N-terminal domain of the prion protein enables highly sensitive protein detection at low concentrations. This novel approach provides a potent and reproducible method for characterizing proteins at nanomolar concentrations.
JOURNAL OF PHYSICAL CHEMISTRY LETTERS
(2021)
Review
Biochemistry & Molecular Biology
Sandeep K. Rai, Adriana Savastano, Priyanka Singh, Samrat Mukhopadhyay, Markus Zweckstetter
Summary: Biomolecular condensation through LLPS has attracted widespread interest, but aberrant phase transitions may be associated with diseases like neurodegeneration. Tau, an important IDP, plays crucial roles in cellular functions and its phase separation may have close links with physiology and disease.
Article
Chemistry, Physical
Priyanka Dogra, Shruti Arya, Avinash K. Singh, Anindya Datta, Samrat Mukhopadhyay
Summary: The conformational plasticity of intrinsically disordered proteins (IDPs) is important for their biological functions, and is governed by chain-chain and chain-solvent interactions. In this study, the conformational and solvation dynamics around the N and C-terminal segments of a protein called Pmel17, which forms functional amyloid responsible for melanin biosynthesis, were characterized using fluorescence measurements. The results showed slight compaction and slower rotational dynamics around the amyloidogenic C-terminal segment compared to the proline-rich N-terminal segment. This compaction was associated with restrained mobility of hydration water. These findings highlight the importance of sequence-dependent chain-solvent interactions in directing the conversion of dynamic IDPs into ordered amyloid assemblies.
JOURNAL OF PHYSICAL CHEMISTRY B
(2022)
Article
Chemistry, Multidisciplinary
Debapriya Das, Lisha Arora, Samrat Mukhopadhyay
Summary: Protein folding and dynamics are influenced by thermal and viscosity-mediated effects, with internal friction playing a crucial role. The study demonstrates that sequence-specific backbone dihedral barriers control local internal friction in proteins, with different amino acid sequences affecting the level of internal friction.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Biochemistry & Molecular Biology
Sayanta Mahapatra, Anusha Sarbahi, Priyanka Madhu, Hema M. Swasthi, Abhishek Sharma, Priyanka Singh, Samrat Mukhopadhyay
Summary: This study investigates the role of substoichiometric Hsp104 in the formation and persistence of prefibrillar amyloid seeds. The results show that Hsp104 accelerates the formation of prefibrillar species and prolongs their persistence. In addition, Hsp104-modulated amyloid species have better seeding capability and exhibit distinct structural and dynamical characteristics compared to NM-only amyloids.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Anamika Avni, Ashish Joshi, Anuja Walimbe, Swastik G. Pattanashetty, Samrat Mukhopadhyay
Summary: The authors introduced a unique single-droplet surface-enhanced Raman scattering (SERS) methodology to investigate molecular information within the mesoscopic liquid condensed phase. This study sheds light on the formation and regulation mechanism of biomolecular condensates. The highly sensitive measurements enable the capture of crucial interactions, conformational heterogeneity, and structural distributions.
NATURE COMMUNICATIONS
(2022)
News Item
Biophysics
Sandeep K. Rai, Samrat Mukhopadhyay
BIOPHYSICAL JOURNAL
(2022)
Review
Chemistry, Multidisciplinary
Debapriya Das, Samrat Mukhopadhyay
Summary: Protein folding and dynamics are influenced by both thermal and viscosity effects, including external viscous drag from solvent molecules and internal friction within the polypeptide chain. The physical origin of internal friction in intrinsically disordered proteins remains unclear, with diffusive conformational dynamics dominated by segmental motion of the backbone. Polymer models with internal friction are used to describe the friction in complex biopolymeric systems such as intrinsically disordered proteins.
ACCOUNTS OF CHEMICAL RESEARCH
(2022)
Editorial Material
Biochemistry & Molecular Biology
Samrat Mukhopadhyay
Summary: Intrinsically disordered proteins (IDPs) are a class of proteins that expand the functional repertoire and are associated with various biological functions and human diseases. This thematic issue provides current trends and contemporary views on the unique structural and dynamical characteristics of these proteins, as well as their misfolding behavior, aggregation behavior, and phase transitions into biomolecular condensates.
ESSAYS IN BIOCHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Sandeep K. Rai, Roopali Khanna, Anamika Avni, Samrat Mukhopadhyay
Summary: Biomolecular condensates formed through phase separation play crucial roles in cellular functions and disease. In this study, we investigate the complex coacervation of neuronal proteins tau and prion, driven by specific electrostatic interactions and characterized by dynamic liquid-like droplets. We employ a combination of time-resolved tools to reveal the formation of heterotypic condensates with domain-specific electrostatic nanoclusters. These condensates can be modulated by RNA, resulting in reversible, multiphasic ternary condensates of different morphologies. Aging leads to the conversion of droplets into solid-like co-assemblies, accompanied by the formation of amorphous and amyloid-like co-aggregates. Our findings provide mechanistic insights into the role of tau and PrP in neuropathology and highlight the broader biological significance of complex phase transitions.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Biochemistry & Molecular Biology
Sayanta Mahapatra, Anusha Sarbahi, Neha Punia, Ashish Joshi, Anamika Avni, Anuja Walimbe, Samrat Mukhopadhyay
Summary: Prion-like self-perpetuating conformational conversion of proteins into amyloid aggregates is influenced by ATP molecules, which can both accelerate aggregation and disaggregate preformed fibrils. ATP modulates the formation and dissolution of amyloids and restricts autocatalytic amplification by controlling the amount of fragmentable and seeding-competent aggregates. Furthermore, ATP can promote phase separation-mediated aggregation of proteins harboring prion-like domains. These findings provide important mechanistic insights into the concentration-dependent chemical chaperoning by ATP against prion-like transmissions of amyloids.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Archit Gupta, Ashish Joshi, Kanika Arora, Samrat Mukhopadhyay, Purnananda Guptasarma
Summary: The bacterial chromosome, known as its nucleoid, is an amorphous assemblage of globular nucleoprotein domains that exist as an irregularly-shaped, membrane-less, intracellular compartment separated from the cell's cytoplasm. Two abundant nucleoid-associated proteins, HU and Dps, undergo spontaneous complex coacervation with different forms of DNA/RNA, causing condensation and compaction of nucleic acids into liquid-liquid phase separated condensates in vitro. These complex coacervation modes may serve as models for understanding the in vivo relationships among nucleoid-associated proteins, explaining the presence of multiple isoforms of HU and the roles of HU and Dps in E. coli growth.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Chemistry, Physical
Anamika Avni, Ashish Joshi, Samrat Mukhopadhyay
Summary: Vibrational Raman spectroscopy coupled with hydrogen/deuterium exchange can discern key structural features responsible for diverse amyloid polymorphs. This noninvasive and label-free method allows for the structural differentiation of distinct amyloid polymorphs, capturing conformational heterogeneity and structural distributions. This research provides insights into the molecular factors governing structural diversity in amyloid polymorphs and could potentially simplify the study of amyloid remodeling by small molecules.
JOURNAL OF PHYSICAL CHEMISTRY LETTERS
(2023)