Review
Neurosciences
Alessio Crestini, Francesca Santilli, Stefano Martellucci, Elena Carbone, Maurizio Sorice, Paola Piscopo, Vincenzo Mattei
Summary: Specific protein misfolding and aggregation are mechanisms underlying neurodegenerative diseases such as prion disease and Alzheimer's disease (AD). The misfolded proteins contribute to the pathological features of AD, including the formation of plaques and neurofibrillary tangles. The cellular prion protein (PrPC) has an important role in the pathogenesis of AD.
JOURNAL OF ALZHEIMERS DISEASE
(2022)
Review
Neurosciences
Narendran Annadurai, Juan B. De Sanctis, Marian Hajduch, Viswanath Das
Summary: The spread of tau pathology in AD mainly occurs through a prion-like manner between cells. The secretion pathway of tau involves unconventional secretory pathways, such as non-vesicular and vesicular mechanisms, leading to tau release into the extracellular space. Further research is needed to understand these pathways for the development of therapeutic approaches targeting prion-like tau forms in AD.
EXPERIMENTAL NEUROLOGY
(2021)
Article
Geriatrics & Gerontology
Sara Lopez-Garcia, Carmen Lage, Ana Pozueta, Maria Garcia-Martinez, Martha Kazimierczak, Andrea Fernandez-Rodriguez, Maria Bravo, Luis Reyes-Gonzalez, Juan Irure, Marcos Lopez-Hoyos, Eloy Rodriguez-Rodriguez, Pascual Sanchez-Juan
Summary: Reduced sleep time is a predictor of higher levels of tau proteins, particularly in APOE ε4 carriers. Total sleep time estimated by actigraphy may serve as an early biomarker of tau pathology.
FRONTIERS IN AGING NEUROSCIENCE
(2021)
Article
Biochemistry & Molecular Biology
Paulo J. da Costa, Malika Hamdane, Luc Buee, Franck Martin
Summary: Tau proteins play a crucial role in regulating microtubule dynamics and are also involved in various functions in neurons. Abnormal tau mRNA metabolism, expression, and post-translational modifications are critical steps in the pathogenicity of tau proteins. Recent research has highlighted the relevance of tau function to general mRNA metabolism.
Article
Neurosciences
Youssra K. K. Al-Hilaly, Connor Hurt, Janet E. E. Rickard, Charles R. R. Harrington, John M. D. Storey, Claude M. M. Wischik, Louise C. C. Serpell, Ansgar B. B. Siemer
Summary: Aggregation of the tau protein into fibrillar cross-beta aggregates is a characteristic of neurodegenerative diseases like Alzheimer's disease. A recent study found that a tau fragment called dGAE can form filaments in vitro, providing a promising model for studying AD tau filaments. Solid-state NMR was used to characterize the tau filaments and it was found that filaments assembled under non-reducing conditions are more dynamic and less ordered than those assembled in the presence of a reducing agent.
FRONTIERS IN NEUROSCIENCE
(2022)
Article
Neurosciences
Shu-Yu Liang, Zuo-Teng Wang, Lan Tan, Jin-Tai Yu
Summary: This article introduces the function and dysfunction of microtubule-associated protein tau in the central nervous system and discusses its role in neurodegenerative diseases, tau phosphorylation-related enzymes and proteins, and its relationship with cell dysfunction. The study of tau neurotoxicity provides new directions for the treatment of tauopathies.
MOLECULAR NEUROBIOLOGY
(2022)
Article
Neurosciences
Kayo Yukawa, Satomi Yamamoto-Mcguire, Louis Cafaro, Christine Hong, Fredrik Kamme, Tsuneya Ikezu, Seiko Ikezu
Summary: TTBK1 is an attractive therapeutic target in the early stages of AD, as it can delay the progression of tau pathology by suppressing the expression of phosphorylated tau.
ACTA NEUROPATHOLOGICA COMMUNICATIONS
(2023)
Review
Biochemistry & Molecular Biology
Hui-Liang Zhang, Xiao-Chuan Wang, Rong Liu
Summary: Zinc is crucial for human growth and development, particularly in regulating the mechanisms of neurodegenerative diseases.
Article
Agriculture, Multidisciplinary
Jingxin Chen, Wanyao Ma, Jiangchuan Yu, Xi Wang, Hongling Qian, Ping Li, Haiqiong Ye, Yue Han, Zhengding Su, Meng Gao, Yongqi Huang
Summary: This study found that the green tea polyphenol EGCG promotes the formation of liquid tau droplets by interacting with the proline-rich domain of tau through hydrophobic interactions and hydrogen bonds. The oxidation of EGCG, tau phosphorylation, and the chemical structure of polyphenols all influence the effectiveness of EGCG in facilitating tau liquid-liquid phase separation (LLPS). These findings provide new insights into the biological activity of EGCG and suggest potential mechanisms for its role in alleviating neurodegenerative diseases.
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
(2023)
Article
Endocrinology & Metabolism
Ji Hee Kim, Heui Seung Lee, Yoo Hwan Kim, Mi Jung Kwon, Joo-Hee Kim, Chan Yang Min, Dae Myoung Yoo, Hyo Geun Choi
Summary: This nested case-control study investigated the associations between thyroid diseases and Alzheimer's disease (AD). The results showed that hypothyroidism, thyroiditis, and hyperthyroidism had significantly higher prevalence rates in AD patients compared to the control group.
FRONTIERS IN ENDOCRINOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Rosalia Bruno, Geraldina Riccardi, Floriana Iacobone, Flavia Chiarotti, Laura Pirisinu, Ilaria Vanni, Stefano Marcon, Claudia D'Agostino, Matteo Giovannelli, Piero Parchi, Umberto Agrimi, Romolo Nonno, Michele Angelo Di Bari
Summary: This study investigated the relationship between prion strains and astrocyte phenotype in six human- and animal-vole-adapted strains. The results showed that astrocyte morphology and astrocyte-associated PrPSc deposition varied depending on the strain, indicating strain-specific phenotypes of reactive astrocytes. Additionally, astrocyte-associated PrPSc deposition was observed in four out of six strains and correlated with astrocyte size.
Article
Biochemistry & Molecular Biology
Jacob F. Wardman, Lyann Sim, Jennifer Liu, Teresa A. Howard, Andreas Geissner, Phillip M. Danby, Alisdair B. Boraston, Warren W. Wakarchuk, Stephen G. Withers
Summary: Mucin-type O-glycosylation is an important post-translational modification involved in cellular communication. However, the study of O-glycoproteins and O-glycans is challenging due to the lack of available enzymes for their assembly and degradation. To overcome this, a genetically encoded screening method was developed using engineered Escherichia coli to screen for enzymes that act on O-glycoproteins. The method uses an O-glycosylated fluorescence resonance energy transfer probe as a read-out of glycosylation state and can also assay glycosidases and glycosyltransferases. The methodology has potential for the directed evolution of O-glycopeptidases.
NATURE CHEMICAL BIOLOGY
(2023)
Review
Chemistry, Analytical
Arezoo Mirzaie, Hassan Nasrollahpour, Balal Khalilzadeh, Ali Akbar Jamali, Raymond J. Spiteri, Hadi Youse, Ibrahim Isildak, Reza Rahbarghazi
Summary: Alzheimer's disease is a prevalent neurodegenerative disorder characterized by progressive deterioration, loss of neurons, and cognitive decline. Amyloid beta and Tau proteins are key biomarkers of the disease, and their abnormal levels in biofluids, particularly cerebrospinal fluid, are directly linked to the incidence and progression of Alzheimer's. Developing sensitive and reliable methods for screening and evaluating these biomarkers in cerebrospinal fluid can aid in early diagnosis and treatment. This article discusses the impact of Alzheimer's on cerebrospinal fluid and provides an overview of the latest biosensors for detecting amyloid beta and Tau in cerebrospinal fluid samples.
TRAC-TRENDS IN ANALYTICAL CHEMISTRY
(2023)
Review
Neurosciences
Juan S. Jimenez
Summary: The molecular events leading to the appearance of filamentous forms of phosphorylated tau protein in neurodegenerative diseases (tauopathies) are still unknown, as well as the causal relationship between these events and initial symptoms. The main function of tau protein in neurons is controversial, but it appears to have multiple functions. It interacts with various macromolecules and proteins, participating in the regulation of microtubules, nuclear localization and DNA, synaptic activity, RNA metabolism, fats transport, proteostasis, amyloid cascade hypothesis, mitochondria, phosphorylation, and more. The interactome studies reveal numerous partners of tau, indicating its involvement in a complex network of regulatory interactions.
Article
Neurosciences
Zuha Waheed, Jawaria Choudhary, Faria Hasan Jatala, Aneeqa Noor, Inga Zerr, Saima Zafar
Summary: Tau is a microtubule-associated binding protein in the nervous system that stabilizes microtubules in nerve cells. It accumulates as aggregates and tangles, leading to various pathologies. Different splice variants of tau are expressed in the brain and contribute to neurodegenerative diseases. The isoforms have different roles and undergo post-translational modifications at different rates, affecting their physiological and pathological attributes. This article aims to review the roles of tau isoforms and their underlying mechanisms in neurological deficits.
MOLECULAR NEUROBIOLOGY
(2023)
Article
Biochemical Research Methods
Miao Xu, Manisha Pradhan, Kirill Gorshkov, Jennifer D. Petersen, Min Shen, Hui Guo, Wei Zhu, Carleen Klumpp-Thomas, Sam Michael, Misha Itkin, Zina Itkin, Marco R. Straus, Joshua Zimmerberg, Wei Zheng, Gary R. Whittaker, Catherine Z. Chen
Summary: In this study, a cell-based SARS-CoV-2 entry assay using viral pseudotyping was established and several active compounds inhibiting SARS-CoV-2 entry were identified. The assay demonstrated its utility in the discovery and development of entry inhibitors and the mechanistic study of anti-SARS-CoV-2 compounds.
Review
Pharmacology & Pharmacy
Deborah K. Ngan, Tuan Xu, Menghang Xia, Wei Zheng, Ruili Huang
Summary: This study analyzed the correlation between the activity profiles of approved drugs and their anti-SARS-CoV-2 activity. The study found a significant correlation between the activity profiles of hERG, PLD, and cytotoxicity screens and anti-SARS-CoV-2 activity. The findings help identify preferred drug candidates and avoid potential toxicity.
DRUG DISCOVERY TODAY
(2022)
Article
Oncology
Junjie Hong, Yu-Shan Cheng, Shu Yang, Manju Swaroop, Miao Xu, Jeanette Beers, Jizhong Zou, Wenwei Huang, Juan J. Marugan, Xiujun Cai, Wei Zheng
Summary: In this study, induced pluripotent stem cell (iPSC) lines were generated from MPS II patient-derived dermal fibroblast cell lines. These iPSC lines exhibited typical disease features and were used as a cell-based disease model to evaluate drug efficacy and screen compounds for drug development. Enzyme replacement therapy and certain drugs showed positive effects in partially rescuing the disease phenotypes of MPS II cells.
EXPERIMENTAL CELL RESEARCH
(2022)
Article
Chemistry, Medicinal
Peng Gao, Miao Xu, Qi Zhang, Catherine Z. Chen, Hui Guo, Yihong Ye, Wei Zheng, Min Shen
Summary: This study developed a GCN-based virtual screening workflow that can rapidly identify new small molecule inhibitors against validated drug targets by training the model using information from experimentally identified HSPG and actin inhibitors.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Chemistry, Medicinal
Tuan Xu, Miao Xu, Wei Zhu, Catherine Z. Chen, Qi Zhang, Wei Zheng, Ruili Huang
Summary: Machine learning models were developed to identify anti-SARS-CoV-2 compounds, which showed good performance and significantly improved the efficiency of drug screening compared to the original methods.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Qi Zhang, Peter Radvak, Juhyung Lee, Yue Xu, Vivian Cao-Dao, Miao Xu, Wei Zheng, Catherine Z. Chen, Hang Xie, Yihong Ye
Summary: The spike protein of SARS-CoV-2 interacts with heparan sulfate on cell surface, facilitating viral entry. Mitoxantrone inhibits the fusogenic function of spike and effectively prevents SARS-CoV-2 infection in cell-based models and human lung tissues. Mitoxantrone analogs with reduced DNA topoisomerase affinity may offer an alternative therapy for breakthrough infections in the post-vaccine era.
SCIENTIFIC REPORTS
(2022)
Article
Chemistry, Medicinal
Jonathan H. Shrimp, John Janiszewski, Catherine Z. Chen, Miao Xu, Kelli M. Wilson, Stephen C. Kales, Philip E. Sanderson, Paul Shinn, Rick Schneider, Zina Itkin, Hui Guo, Min Shen, Carleen Klumpp-Thomas, Samuel G. Michael, Wei Zheng, Anton Simeonov, Matthew D. Hall
Summary: This study developed a suite of biochemical assays for the discovery and development of new inhibitors of TMPRSS2. Through drug repurposing, a total of 6030 compounds were screened biochemically, and the potential antiviral compounds were evaluated in cell-based experiments.
ACS INFECTIOUS DISEASES
(2022)
Article
Cell Biology
Tamara Marin, Andres E. Dulcey, Fabian Campos, Catalina de la Fuente, Mariana Acuna, Juan Castro, Claudio Pinto, Maria Jose Yanez, Cristian Cortez, David W. McGrath, Pablo J. Saez, Kirill Gorshkov, Wei Zheng, Noel Southall, Maria Carmo-Fonseca, Juan Marugan, Alejandra R. Alvarez, Silvana Zanlungo
Summary: Niemann-Pick type A (NPA) disease is a fatal lysosomal neurodegenerative disorder. Recent studies have shown that c-Abl tyrosine kinase activity plays a role in neuronal damage and death in NPA disease. There is potential for the use of c-Abl inhibitors in the clinical treatment of NPA patients.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Chemistry, Medicinal
Kevin J. Frankowski, Samarjit Patnaik, Chen Wang, Noel Southall, Dipannita Dutta, Soumitta De, Dandan Li, Christopher Dextras, Yi-Han Lin, Marthe Bryant-Connah, Danielle Davis, Feijun Wang, Leah M. Wachsmuth, Pranav Shah, Jordan Williams, Md Kabir, Edward Zhu, Bolormaa Baljinnyam, Amy Wang, Xin Xu, John Norton, Marc Ferrer, Steve Titus, Anton Simeonov, Wei Zheng, Lesley A. Mathews Griner, Ajit Jadhav, Jeffrey Aube, Mark J. Henderson, Udo Rudloff, Frank J. Schoenen, Sui Huang, Juan J. Marugan
Summary: The perinucleolar compartment (PNC) is a subnuclear body enriched with RNA transcripts and RNA-binding proteins. PNC prevalence is positively correlated with cancer progression and metastatic capacity. A high-throughput assay was developed to identify small molecules that can reduce PNC prevalence in cancer cells. The discovery of the pyrrolopyrimidine series led to the identification of the bioavailable analogue metarrestin, which has potent antimetastatic activity.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Ying Fu, Juliana da Fonseca Rezende e Mello, Bryan D. D. Fleming, Alex Renn, Catherine Z. Z. Chen, Xin Hu, Miao Xu, Kirill Gorshkov, Quinlin Hanson, Wei Zheng, Emily M. M. Lee, Lalith Perera, Robert Petrovich, Manisha Pradhan, Richard T. T. Eastman, Zina Itkin, Thomas B. B. Stanley, Allen Hsu, Venkata Dandey, Kedar Sharma, William Gillette, Troy Taylor, Nitya Ramakrishnan, Shelley Perkins, Dominic Esposito, Eunkeu Oh, Kimihiro Susumu, Mason Wolak, Marc Ferrer, Matthew D. D. Hall, Mario J. J. Borgnia, Anton Simeonov
Summary: The study presents a rapid and efficient strategy for developing neutralizing humanized nanobody constructs against SARS-CoV-2. The most potent nanobody identified is capable of neutralizing the B.1.1.7 variant and withstands a specific mutation. Structural analysis and molecular dynamics simulations provide insights into the neutralization process. In an ex vivo model, the nanobody treatment effectively reduces viral burden for different SARS-CoV-2 strains.
Article
Biochemistry & Molecular Biology
Phillip R. Sanchez, Sarah A. Head, Shan Qian, Haibo Qiu, Avishek Roy, Zhendong Jin, Wei Zheng, Jun O. Liu
Summary: ZJ-101, a simplified analog of superstolide A, exhibits potent antiproliferative and antiadhesive effects, making it a potential therapeutic agent. Transcriptomics analysis revealed a unique dysregulation of the endomembrane system by ZJ-101, including selective inhibition of O-glycosylation. In a triple-negative breast cancer spheroid model, ZJ-101 showed potential for reversing 3D-induced chemoresistance, indicating its synergistic therapeutic potential.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Multidisciplinary Sciences
Ivan Pavlinov, Mitali Tambe, Joshua Abbott, Ha Nam Nguyen, Miao Xu, Manisha Pradhan, Atena Farkhondeh, Wei Zheng
Summary: The ability to model human neurological tissues in vitro is crucial for drug development in neurological disorders. iPSC-derived brain organoids can effectively mimic protein expression patterns and physiology of specific brain regions. This study differentiated midbrain-specific brain organoids from iPSC-lines derived from healthy individuals using a matrix-free, bioreactor method. The expression of midbrain-specific neuronal markers was monitored from 7 to 90 days, and the organoids were further characterized using electron microscopy and RNA-seq. The findings provide potential benchmarks for evaluating differentiation protocols and identifying disease phenotypes in midbrain organoids derived from patient iPSC-lines with genetic neurological disorders.
Article
Chemistry, Medicinal
Kirill Gorshkov, Desarey Morales Vasquez, Kevin Chiem, Chengjin Ye, Bruce Nguyen Tran, Juan Carlos de la Torre, Thomas Moran, Catherine Z. Chen, Luis Martinez-Sobrido, Wei Zheng
Summary: This study reports a time-resolved fluorescence resonance energy transfer-based assay for detecting the SARS-CoV-2 nucleocapsid protein. This assay can be used for rapid compound screening and drug efficacy evaluation, and is of great importance for accelerating COVID-19 drug development.
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2022)
Article
Chemistry, Medicinal
Sankalp Jain, Daniel C. Talley, Bolormaa Baljinnyam, Jun Choe, Quinlin Hanson, Wei Zhu, Miao Xu, Catherine Z. Chen, Wei Zheng, Xin Hu, Min Shen, Ganesha Rai, Matthew D. Hall, Anton Simeonov, Alexey Zakharov
Summary: By utilizing NCATS screening data and various models, active small molecules against SARS-CoV-2 were successfully predicted. Further investigation revealed three novel chemotypes with potential, along with the identification of potential host inhibitors.
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2021)
Article
Microbiology
Seung Bum Park, Parker Irvin, Zongyi Hu, Mohsin Khan, Xin Hu, Qiru Zeng, Catherine Chen, Miao Xu, Madeleine Leek, Ruochen Zang, James Brett Case, Wei Zheng, Siyuan Ding, T. Jake Liang
Summary: Two hepatitis C virus fusion inhibitors have been found to broadly block human coronavirus entry into various cell types, showing effective antiviral activity against SARS-CoV-2 and its variants.