Article
Neurosciences
Yan-Zhe Liao, Jing Ma, Jie-Zhi Dou
Summary: In recent years, it has been discovered that more and more neurodegenerative diseases exhibit abnormal expression of the TDP-43 protein, including depletion of TDP-43 in the nucleus and accumulation of TDP-43 in the cytoplasm. This TDP-43 proteinopathy suggests the important role of TDP-43 in the pathogenesis of these diseases, and further research is needed to understand the complex pathophysiological mechanisms of TDP-43 in neurodegenerative diseases.
MOLECULAR NEUROBIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Sean S. Keating, Adekunle T. Bademosi, Rebecca San Gil, Adam K. Walker
Summary: Aggregation of TDP-43 is the hallmark of neurodegenerative diseases, involving depletion, mislocalisation, and post-translational modification of normal nuclear TDP-43. Oxidative stress triggers liquid-liquid phase separation of TDP-43, while RNA-binding deficiency and acetylation mimicry lead to sequestration of normal nuclear TDP-43 into dynamic anisosomes. Nuclear or cytoplasmic aggregation-prone TDP-43 mutants form phosphorylated inclusions that immobilize and insolubilize endogenous TDP-43, indicating pathological transition. Overall, these findings highlight the importance of RNA-binding deficiency and post-translational modifications in driving TDP-43 aggregation and dysfunction in neurodegenerative diseases.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2023)
Correction
Clinical Neurology
Manuela Neumann, Petra Frick, Francesca Paron, Jonas Kosten, Emanuele Buratti, Ian R. Mackenzie
Summary: The originally planned amino acid residues 368-379 for antibody production in TDP-43 protein sequence were incorrectly assigned to 362-373 by the contracted company, resulting in the synthesis and use of a peptide with a phosphorylated serin at 369 instead of 375.
ACTA NEUROPATHOLOGICA
(2021)
Article
Biochemistry & Molecular Biology
Lara A. Gruijs da Silva, Francesca Simonetti, Saskia Hutten, Henrick Riemenschneider, Erin L. Sternburg, Lisa M. Pietrek, Jakob Gebel, Volker Doetsch, Dieter Edbauer, Gerhard Hummer, Lukas S. Stelzl, Dorothee Dormann
Summary: This translated article investigates the regulatory role of post-translational modifications (PTMs) on protein phase separation and aggregation. The study finds that hyperphosphorylation of TDP-43 protein has a protective effect, reducing aggregation and making the condensates more liquid-like and dynamic.
Review
Clinical Neurology
Arenn F. Carlos, Keith A. Josephs
Summary: This paper reviews how FTLD-TDP was established and defined clinically and neuropathologically throughout the past century.
JOURNAL OF NEUROLOGY
(2022)
Article
Biochemistry & Molecular Biology
Meng-Jie Zhao, Xiao Yao, Ping Wei, Chen Zhao, Meng Cheng, Dong Zhang, Wen Xue, Wen-Tian He, Weili Xue, Xinxin Zuo, Lei-Lei Jiang, Zhiyuan Luo, Jiaqi Song, Wen-Jie Shu, Han-Ye Yuan, Yi Liang, Hui Sun, Yan Zhou, Yu Zhou, Ling Zheng, Hong-Yu Hu, Jiwu Wang, Hai-Ning Du
Summary: Research has shown that O-GlcNAc transferase OGT-mediated O-GlcNAcylation of TDP-43 can suppress ALS-related proteinopathies and enhance TDP-43's splicing function. This study further demonstrates the importance of TDP-43 O-GlcNAcylation in maintaining neuronal health and function.
Article
Chemistry, Medicinal
Praveen P. N. Rao, Arash Shakeri, Yusheng Zhao, Frederic Calon
Summary: TDP-43 is a protein involved in various physiological processes and diseases, known collectively as TDP-43 proteinopathies. Recent research has deepened our understanding of its structure and function, with solved structures providing insights for designing ligands to study, diagnose, and treat TDP-43 proteinopathies.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Neurosciences
Axel Meneses, Shunsuke Koga, Justin O'Leary, Dennis W. Dickson, Guojun Bu, Na Zhao
Summary: TDP-43, a protein encoded by the TARDBP gene, plays a crucial role in various neurodegenerative diseases such as ALS, FTLD, and AD. Its pathology is associated with cognitive impairment severity and genetic risk factors, such as APOE4, in AD.
MOLECULAR NEURODEGENERATION
(2021)
Article
Chemistry, Multidisciplinary
Lixin Yang, Yllza Jasiqi, Agnes Zettor, Oscar Vadas, Jeanne Chiaravalli, Fabrice Agou, Hilal A. Lashuel
Summary: The native state stabilization of TDP-43 is a viable strategy for treating TDP-43 proteinopathies. By designing C-terminal substitutions and binding native oligonucleotide ligands, the monomeric state of TDP-43 can be stabilized and prevent aggregation and phase separation.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Review
Biochemistry & Molecular Biology
Han-Jou Chen, Jacqueline C. Mitchell
Summary: TDP-43 protein is strongly linked to the pathogenesis of neurodegenerative disorders, and while mutations in the TARDBP gene may cause disease in a small subset of patients, TDP-43 proteinopathy is present in a majority of cases. Cellular functions such as nucleocytoplasmic transport, protein homeostasis, RNA interactions, and cellular stress play key roles in TDP-43 pathogenesis, with evidence suggesting aggregation-prone TDP-43 can be transmitted intercellularly, contributing to disease spread.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Manami Deshimaru, Mariko Kinoshita-Kawada, Kaori Kubota, Takuya Watanabe, Yasuyoshi Tanaka, Saito Hirano, Fumiyoshi Ishidate, Masaki Hiramoto, Mitsuru Ishikawa, Yoshinari Uehara, Hideyuki Okano, Shinichi Hirose, Shinsuke Fujioka, Katsunori Iwasaki, Junichi Yuasa-Kawada, Takayasu Mishima, Yoshio Tsuboi
Summary: The research identified DCTN1 as a new player in TDP-43 cytoplasmic-nuclear transport, showing that dysregulation of DCTN1-TDP-43 interactions triggers mislocalization and aggregation of TDP-43. This provides insights into the pathological mechanisms of Perry disease and other TDP-43 proteinopathies.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Yi-Syue Tsou, Jing-Huei Lai, Kai-Yun Chen, Cheng-Fu Chang, Chi-Chen Huang
Summary: Stroke is a leading cause of death and disability worldwide, and its negative impact should not be underestimated. While therapies for ischemic stroke, such as thrombolytic recanalization and mechanical thrombectomy, are available and effective, there are still limitations in these interventions. This study shows that pathological TDP-43 plays a role in ischemic stroke by causing impaired mitochondrial function and increased gliosis. Additionally, rapamycin administration in ischemic rats not only decreases pathological TDP-43 levels, but also improves mitochondrial function and reduces cellular apoptosis, suggesting its neuroprotective benefits in ischemic stroke.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Cell Biology
Saebom Lee, Hye Guk Ryu, Sin Ho Kweon, Hyerynn Kim, Hyeonwoo Park, Kyung-Ha Lee, Sang-Min Jang, Chan Hyun Na, Sangjune Kim, Han Seok Ko
Summary: Non-receptor tyrosine kinase c-Abl is involved in the development of various neurodegenerative disorders. This study reveals that TDP-43 is a novel substrate for c-Abl and its phosphorylation by c-Abl leads to increased levels of TDP-43 in the cytoplasm and the formation of stress granules. In addition, phosphorylation of TDP-43 by c-Abl promotes its aggregation and neuronal cell death.
Article
Biochemistry & Molecular Biology
Manuela Perez-Berlanga, Vera Wiersma, Aurelie Zbinden, Laura De Vos, Ulrich Wagner, Chiara Foglieni, Izaskun Mallona, Katharina M. Betz, Antoine Clery, Julien Weber, Zhongning Guo, Ruben Rigort, Pierre de Rossi, Ruchi Manglunia, Elena Tantardini, Sonu Sahadevan, Oliver Stach, Marian Hruska-Plochan, Frederic H-T Allain, Paolo Paganetti, Magdalini Polymenidou
Summary: Aggregation of the RNA-binding protein TDP-43 is the key neuropathological feature of neurodegenerative diseases. Our study reveals that oligomerization and RNA binding play important roles in TDP-43 stability, function, and subcellular localization. We also found that the location of TDP-43 aggregates is determined by different pathways, shedding light on the origins of pathological species observed in TDP-43 proteinopathy patients.
Article
Chemistry, Medicinal
Bharath Raghavan, Florian K. Schackert, Andrea Levy, Sophia K. Johnson, Emiliano Ippoliti, Davide Mandelli, Jogvan Magnus Haugaard Olsen, Ursula Rothlisberger, Paolo Carloni
Summary: MiMiC is a flexible and scalable multiscale modeling framework that combines quantum mechanics (QM) and molecular mechanics (MM) codes. The paragraph introduces MiMiCPy, a user-friendly tool written in Python 3 that automates the preparation of MiMiC input files. It also highlights the modular structure of MiMiCPy, allowing for easy extensions to new program formats.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Biochemistry & Molecular Biology
Shawn C. C. Hsueh, Adekunle Aina, Andrei Yu. Roman, Neil R. Cashman, Xubiao Peng, Steven S. Plotkin
Summary: Effectively presenting epitopes on immunogens is crucial in treating protein misfolding diseases. Computational modeling of cyclic peptide scaffolds can predict their conformational ensembles, allowing for selective targeting of toxic conformations while sparing healthy forms of the protein. Screening and ranking these cyclic peptide scaffolds in silico can provide insights into their suitability as immunogens.
ACS CHEMICAL NEUROSCIENCE
(2022)
Article
Chemistry, Analytical
Elena Zavyalova, Daria Tikhonova, Gleb Zhdanov, Elena Rudakova, Vera Alferova, Andrey Moiseenko, Polina Kamzeeva, Alexei Khrulev, Arthur Zalevsky, Alexander Arutyunyan, Roman Novikov, Vladimir Kukushkin, Andrey Aralov
Summary: Phosphorylated adenosine derivatives play important roles in the energetic balance of the cell, biosynthesis of cell components, and regulation of protein activity. Surface-enhanced Raman spectroscopy (SERS) is an optical method that can provide a unique spectrum of a substance at low concentrations. By using nucleic acid aptamers and Raman-active dyes, the specificity and limit of detection of SERS-based sensors can be significantly increased. In this study, a biosensor based on the AMP-dependent interaction between a DNA aptamer and a novel Raman-active dye was described, showing a low limit of detection and a wide dynamic range.
ANALYTICA CHIMICA ACTA
(2022)
Article
Cell Biology
Laurie Arnaud, Philippe Benech, Louise Greetham, Delphine Stephan, Angelique Jimenez, Nicolas Jullien, Laura Garcia-Gonzalez, Philipp O. Tsvetkov, Francois Devred, Ignacio Sancho-Martinez, Juan Carlos Izpisua Belmonte, Kevin Baranger, Santiago Rivera, Emmanuel Nivet
Summary: This study reveals that APOE ε4 controls inflammation in human astrocytes by regulating TAGLN3 expression and NF-KB activation. APOE4 downregulates TAGLN3, resulting in chronic low-grade inflammation and hyperactivated inflammatory responses. TAGLN3 supplementation can pharmacologically reverse this pro-inflammatory state, and TAGLN3 is confirmed to be downregulated in the brain of patients with sAD.
Article
Biochemistry & Molecular Biology
Viktoriia E. Baksheeva, Philipp O. Tsvetkov, Arthur O. Zalevsky, Vasiliy Vladimirov, Neonila Gorokhovets, Dmitry Zinchenko, Sergei E. Permyakov, Francois Devred, Evgeni Yu Zernii
Summary: Neuronal calcium sensors (NCSs) can complement their calcium sensing activity by sensing zinc fluctuations. Different proteins in the NCS family have varying abilities to bind zinc ions, with some proteins showing conformational changes and regulation of dimeric state in the absence of calcium, while others become insensitive to zinc in the presence of calcium. Based on their zinc-binding properties, NCS proteins can be divided into physiological Ca2+/Zn2+ sensor proteins, pathological Ca2+/Zn2+ sensors, and Zn2+-resistant Ca2+ sensor proteins.
Review
Oncology
Rayane Hedna, Herve Kovacic, Alessandra Pagano, Vincent Peyrot, Maxime Robin, Francois Devred, Gilles Breuzard
Summary: Tau protein plays a crucial role in neurodegenerative diseases, but recent studies have shown its involvement in cancer progression and treatment resistance. This review focuses on the role of Tau in glioblastoma and sheds light on its mechanistic involvement in oncogenic processes. It also discusses the potential of Tau as a therapeutic target for glioblastoma treatment.
Article
Biochemistry & Molecular Biology
Ebrima Gibbs, Beibei Zhao, Andrei Roman, Steven S. Plotkin, Xubiao Peng, Shawn C. C. Hsueh, Adekunle Aina, Jing Wang, Clay Shyu, Calvin K. Yip, Sung-Eun Nam, Johanne M. Kaplan, Neil R. Cashman
Summary: This study aims to generate antibodies that selectively target toxic forms of alpha-Syn. Computational modeling was used to predict conformational epitopes and monoclonal antibodies with the desired binding profile were successfully produced. These antibodies can recognize specific pathological alpha-Syn aggregates and protect neurons from toxic alpha-Syn oligomers.
Article
Biochemistry & Molecular Biology
Dahbia Yatoui, Philipp O. Tsvetkov, Romain La Rocca, Viktoriia E. Baksheeva, Diane Allegro, Gilles Breuzard, Geraldine Ferracci, Deborah Byrne, Francois Devred
Summary: Researchers have identified three zinc binding sites on Tau protein and found that zinc binding to these sites plays an important role in aggregation. Particularly, lack of zinc binding to the high affinity site in the repeat region prevents Tau protein from aggregating.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2022)
Article
Biochemistry & Molecular Biology
Maria Cecilia Gonzalez Garcia, Caroline Radix, Claude Villard, Gilles Breuzard, Pascal Mansuelle, Pascale Barbier, Philipp O. Tsvetkov, Harold De Pomyers, Didier Gigmes, Francois Devred, Herve Kovacic, Kamel Mabrouk, Jose Luis
Summary: In this study, we identified myotoxin-3, a peptide from the venom of the Northern Pacific rattlesnake, as a potential microtubule targeting agent. Myotoxin-3 increased tubulin polymerization and showed slight toxicity against glioblastoma and breast carcinoma cells. It also induced remodeling of the microtubule network and decreased microtubule dynamic instability. These effects were attributed to the direct interaction of myotoxin-3 with tubulin. Our findings suggest that exogenous peptides, such as myotoxin-3, could be promising candidates for the development of new anti-cancer drugs, and venom is a valuable source of pharmacologically active molecules.
Article
Biochemistry & Molecular Biology
Stephen K. Burley, Charmi Bhikadiya, Chunxiao Bi, Sebastian Bittrich, Henry Chao, Li Chen, Paul A. Craig, Gregg Crichlow, Kenneth Dalenberg, Jose M. Duarte, Shuchismita Dutta, Maryam Fayazi, Zukang Feng, Justin W. Flatt, Sai Ganesan, Sutapa Ghosh, David S. Goodsell, Rachel Kramer Green, Vladimir Guranovic, Jeremy Henry, Brian P. Hudson, Igor Khokhriakov, Catherine L. Lawson, Yuhe Liang, Robert Lowe, Ezra Peisach, Irina Persikova, Dennis W. Piehl, Yana Rose, Andrej Sali, Joan Segura, Monica Sekharan, Chenghua Shao, Brinda Vallat, Maria Voigt, Ben Webb, John D. Westbrook, Shamara Whetstone, Jasmine Y. Young, Arthur Zalevsky, Christine Zardecki
Summary: The RCSB PDB is a founding member of the wwPDB and serves as the US data center for the open-access PDB archive. The upgraded RCSB.org web portal provides a one-stop-shop for open access to a large number of experimentally-determined PDB structures and computationally-predicted CSMs, along with related functional annotations.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Oncology
Remi Eyraud, Stephane Ayache, Philipp. O. O. Tsvetkov, Shanmugha Sri Kalidindi, Viktoriia. E. E. Baksheeva, Sebastien Boissonneau, Carine Jiguet-Jiglaire, Romain Appay, Isabelle Nanni-Metellus, Olivier Chinot, Francois Devred, Emeline Tabouret
Summary: Plasma denaturation profiles obtained through nanoDSF can be used with AI algorithms to discriminate EGFR alterations in glioblastoma (GBM), providing a predictive diagnostic biomarker for therapy strategies.
Article
Biochemistry & Molecular Biology
Viktoriia E. Baksheeva, Veronika V. Tiulina, Elena N. Iomdina, Sergey Yu. Petrov, Olga M. Filippova, Nina Yu. Kushnarevich, Elena A. Suleiman, Remi Eyraud, Francois Devred, Marina V. Serebryakova, Natalia G. Shebardina, Dmitry V. Chistyakov, Ivan I. Senin, Vladimir A. Mitkevich, Philipp O. Tsvetkov, Evgeni Yu. Zernii
Summary: Primary open-angle glaucoma (POAG) is a common neurodegenerative disorder that causes blindness and is characterized by optic nerve and retinal ganglion cell damage. Early detection and treatment of the disease are crucial, but difficult due to its asymptomatic nature and lack of objective diagnostic approaches. Recent studies have shown that glaucoma involves complex metabolomic and proteomic changes in eye liquids, including tear fluid. However, the analysis of tear fluid is technically challenging and not suitable for clinical practice.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Virology
Margarita A. Kurnaeva, Arthur O. Zalevsky, Eugene A. Arifulin, Olga M. Lisitsyna, Anna Tvorogova, Maria Y. Shubina, Gleb P. Bourenkov, Maria A. Tikhomirova, Daria M. Potashnikova, Anastasia Kachalova, Yana R. Musinova, Andrey Golovin, Yegor S. Vassetzky, Eugene Sheval
Summary: This study investigated the integration of nuclear localization signal (NLS) and nucleolar localization signal (NoLS) into the basic domain of HIV-1 Tat and found that these two supplementary functions are embedded within the amino acid sequence. Integration of NLSs and NoLSs into functional domains of viral proteins enriched with positively charged amino acids allows the concentration of different functions within small protein regions and may have influenced viral evolution by preventing an increase in protein size.
JOURNAL OF VIROLOGY
(2022)
Article
Biochemistry & Molecular Biology
Margarita N. Baranova, Arsen M. Kudzhaev, Yuliana A. Mokrushina, Vladislav V. Babenko, Maria A. Kornienko, Maja V. Malakhova, Victor G. Yudin, Maria P. Rubtsova, Arthur Zalevsky, Olga A. Belozerova, Sergey Kovalchuk, Yuriy N. Zhuravlev, Elena N. Ilina, Alexander G. Gabibov, Ivan V. Smirnov, Stanislav S. Terekhov
Summary: The biodiversity of microorganisms is maintained by interactions between species, and the functionality of human microbiomes is influenced by aseptic conditions and antibiotic use. Wild animal microbiomes have a protective shield against pathogen invasion. Using ultrahigh-throughput microfluidic technologies, the researchers identified Bacillus pumilus strains in the microbiomes of wild animals that produce antibacterial metabolites, including amicoumacin A, which can inhibit the growth of both Gram-positive and Gram-negative bacteria. The discovery of these strains opens up new opportunities for pathogen control and microbiome remodeling in various industries.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)