Review
Biochemistry & Molecular Biology
Andrea Corsi, Cristina Bombieri, Maria Teresa Valenti, Maria Grazia Romanelli
Summary: Tau microtubule-associated proteins play important roles in neurons and are associated with several neurodegenerative diseases. Recent studies have focused on understanding the regulation of Tau splicing to develop new treatment approaches.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Cell Biology
Daniel Ruiz-Gabarre, Almudena Carnero-Espejo, Jesus Avila, Vega Garcia-Escudero
Summary: Tau protein, encoded by the MAPT gene, has multiple physiological functions and is associated with various pathologies. The splicing of MAPT transcripts is complex, generating multiple isoforms that are spatially and developmentally regulated. These Tau isoforms play important roles in both physiology and pathology.
Article
Clinical Neurology
Manuel Schweighauser, Holly J. Garringer, Therese Klingstedt, K. Peter R. Nilsson, Masami Masuda-Suzukake, Jill R. Murrell, Shannon L. Risacher, Ruben Vidal, Sjors H. W. Scheres, Michel Goedert, Bernardino Ghetti, Kathy L. Newell
Summary: Two siblings with a deletion mutation at K281 of MAPT gene developed frontotemporal dementia. Autopsy revealed numerous hyperphosphorylated 3R Tau inclusions in neurons and glial cells of the neocortex and some subcortical regions, including the hippocampus, caudate/putamen, and globus pallidus. These inclusions were argyrophilic with Bodian silver staining but not Gallyas-Braak silver staining. They were not labeled by an antibody specific for tau phosphorylation at S262 and/or S356. Luminescent conjugated oligothiophene HS-84 stained the inclusions, but bTVBT4 did not. Electron cryo-microscopy showed that the core of tau filaments consisted of residues K254-F378 of 3R Tau and was indistinguishable from Pick's disease. We conclude that the MAPT mutation at K281 leads to Pick's disease.
ACTA NEUROPATHOLOGICA
(2023)
Article
Neurosciences
Mette Habekost, Per Qvist, Mark Denham, Ida E. Holm, Arne Lund Jorgensen
Summary: The study reveals that induced neurons from reprogramming of other cell types need extended in vitro culture to express tau isoforms characteristic of adult neurons; Research on porcine and murine cerebral cortices shows age-dependent and species-specific isoform composition of MAPT; Induced neurons directly converted from fibroblasts exhibit developmental patterns of isoform composition related to the pathogenesis of Alzheimer's disease.
MOLECULAR NEUROBIOLOGY
(2021)
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
Biology
Jayashree Kumar, Lela Lackey, Justin M. Waldern, Abhishek Dey, Anthony M. Mustoe, Kevin M. Weeks, David H. Mathews, Alain Laederach, Jonathan P. Staley
Summary: Splicing is a highly regulated process affected by multiple factors, making it challenging to predict the effects of mutations on pre-mRNA structure and function. In this study, a novel chemical probing strategy was used to visualize endogenous precursor and mature MAPT mRNA structures in cells, allowing for predictions of mutation consequences on pre-mRNA structure. Cryo-EM structures of the spliceosome were also analyzed to predict alternative splicing outcomes, achieving high accuracy. A beta-regression weighting framework incorporating splice site strength, RNA structure, and splicing regulatory elements was developed, enabling accurate prediction of the effects of known and newly discovered mutations on MAPT splicing.
Article
Multidisciplinary Sciences
Tebbe de Vries, William Martelly, Sebastien Campagne, Kevin Sabath, Chris P. Sarnowski, Jason Wong, Alexander Leitner, Stefanie Jonas, Shalini Sharma, Frederic H. -T. Allain
Summary: This study determined the 3D structure of the complex between SF3A1-UBL and U1-SL4 RNA and revealed the sequence-specific recognition of U1-SL4 by SF3A1-UBL. The results expand our understanding of RNA binding domains and demonstrate the specific binding capacity of RGG/RG motifs to RNA.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Clinical Neurology
Laura Williams, Diana A. Olszewska, Conor Fearon, Brian Magennis, Allan McCarthy, Lewis P. Rowland, Richard Mayeux, Rory Page, Stanley Fahn, Alan Beausang, Tim Lynch
Summary: Ondine's curse is a rare condition causing failure of automatic respiratory drive, sometimes associated with FTDP-17t. Despite variants affecting different regions of MAPT, patients experienced central hypoventilation during their disease course.
MOVEMENT DISORDERS CLINICAL PRACTICE
(2021)
Article
Neurosciences
Itzhak Fischer
Summary: The MAPT gene can produce multiple isoforms of the tau protein through alternative splicing, with differential expression in specific areas of the nervous system and at different developmental stages. A unique isoform known as Big tau, containing the large exon 4a, has been shown to have distinct structural features. Through a comparative study of the evolution of the MAPT gene, it was discovered that the 4a exon variants appeared early in vertebrate evolution and underwent independent evolution in different species. The appearance of significantly larger variants of tau emphasizes the need for an elongated domain across vertebrate species, potentially related to novel physiological functions and neurodegeneration.
FRONTIERS IN MOLECULAR NEUROSCIENCE
(2022)
Article
Biology
Sarah R. Hansen, David S. White, Mark Scalf, Ivan R. Correa, Lloyd M. Smith, Aaron A. Hoskins, Jonathan P. Staley
Summary: This study investigated the pathway of 5' SS selection by purified yeast U1 snRNP using colocalization single-molecule spectroscopy. The results revealed a sequence-dependent, two-step mechanism for U1 to reversibly select 5' SS, providing a kinetic basis for how U1 may rapidly surveil nascent transcripts for 5' SS.
Article
Biochemistry & Molecular Biology
Katharina Woess, Yuchen Sun, Hanae Morio, Anna Stierschneider, Anna Kaufmann, Stefan Hainzl, Lisa Trattner, Thomas Kocher, Birgit Tockner, Victoria Leb-Reichl, Markus Steiner, Gabriele Brachtl, Andrew P. South, Johann W. Bauer, Julia Reichelt, Tomomi Furihata, Verena Wally, Ulrich Koller, Josefina Pinon Hofbauer, Christina Guttmann-Gruber
Summary: Conventional anti-cancer therapies lack tumor specificity and can result in iatrogenic effects. Spliceosome-mediated RNA trans-splicing (SMaRT) is a promising approach that can target tumor cells while sparing normal cells. This study demonstrates the potential of SMaRT using the RNA trans-splicing molecule RTM44 to target the cancer gene Ct-SLCO1B3 in aggressive skin cancer.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Karli A. Lipinski, Jing Chi, Xin Chen, Aaron A. Hoskins, David A. Brow
Summary: U6 small nuclear RNA (snRNA) is a highly conserved component of spliceosomes. It has been traditionally thought that U6 snRNA is synthesized by RNA polymerase III (RNAP III). However, this study demonstrates that U6 snRNA can also be synthesized by RNA polymerase II (RNAP II). The ability to synthesize U6 snRNA with RNAP II provides more flexibility in controlling U6 levels. Furthermore, the formation of U6 snRNPs containing the Sm complex suggests that U6 snRNA synthesized by RNAP II is functional in vivo.
Article
Biochemistry & Molecular Biology
Ruozhen Wu, Dingwei Zhou, Xin Shen, Feng Chen, Fei Liu, Jianlan Gu
Summary: The study shows that phosphorylation of TDP-43 at specific sites by CK1 epsilon can impact its function in tau mRNA processing, with blocking mutations leading to increased cytoplasmic aggregation of TDP-43 and mimicking mutations enhancing this effect.
JOURNAL OF NEUROCHEMISTRY
(2021)
Article
Cell Biology
Giuseppina Covello, Kavitha Siva, Valentina Adami, Michela Alessandra Denti
Summary: Nucleic acid therapeutics have shown significant progress, but few drugs target RNA splicing modulation. To address this, researchers developed HCS-Splice, a robust cell-based High-Content Screening (HCS) assay. By utilizing a fluorescent splicing reporter plasmid, HCS-Splice provides a versatile and effective strategy for identifying splicing-modulating molecules. It can also be used for functional confirmation of splicing mutations and screening drug candidates. In a proof-of-concept study, HCS-Splice successfully evaluated the efficacy of an exon 10-targeting siRNA in restoring correct alternative splicing balance.
Article
Multidisciplinary Sciences
Constantin Cretu, Patricia Gee, Xiang Liu, Anant Agrawal, Tuong-Vi Nguyen, Arun K. Ghosh, Andrew Cook, Melissa Jurica, Nicholas A. Larsen, Vladimir Pena
Summary: Chemical modulation of intron selection has emerged as a route for cancer therapy. The structures of the U2 snRNP's SF3B module and prespliceosome - both in complexes with splicing modulators - provide insight into the mechanisms of intron recognition and branch site inactivation.
NATURE COMMUNICATIONS
(2021)
Article
Neurosciences
Valentina Lacovich, Sonia L. Espindola, Matias Alloatti, Victorio Pozo Devoto, Lucas E. Cromberg, Maria E. Carna, Giancarlo Forte, Jean-Marc Gallo, Luciana Bruno, Gorazd B. Stokin, M. Elena Avale, Tomas L. Falzone
JOURNAL OF NEUROSCIENCE
(2017)
Article
Geriatrics & Gerontology
Michael Niblock, Tibor Hortobagyi, Claire Troakes, Safa Al-Sarraj, Carl Spickett, Rebecca Jones, Christopher E. Shaw, Jean-Marc Gallo
NEUROBIOLOGY OF AGING
(2016)
Article
Neurosciences
Michael Niblock, Bradley N. Smith, Youn-Bok Lee, Valentina Sardone, Simon Topp, Claire Troakes, Safa Al-Sarraj, Claire S. Leblond, Patrick A. Dion, Guy A. Rouleau, Christopher E. Shaw, Jean-Marc Gallo
ACTA NEUROPATHOLOGICA COMMUNICATIONS
(2016)
Article
Biochemistry & Molecular Biology
Youn-Bok Lee, Pranetha Baskaran, Jorge Gomez-Deza, Han-Jou Chen, Agnes L. Nishimura, Bradley N. Smith, Claire Troakes, Yoshitsugu Adachi, Alan Stepto, Leonard Petrucelli, Jean-Marc Gallo, Frank Hirth, Boris Rogelj, Sarah Guthrie, Christopher E. Shaw
HUMAN MOLECULAR GENETICS
(2017)
Review
Neurosciences
Holly V. Barker, Michael Niblock, Youn-Bok Lee, Christopher E. Shaw, Jean-Marc Gallo
FRONTIERS IN CELLULAR NEUROSCIENCE
(2017)
Article
Cell Biology
Sonia Lorena Espindola, Ana Damianich, Rodrigo Javier Alvarez, Manuela Sartor, Juan Emilio Belforte, Juan Esteban Ferrario, Jean-Marc Gallo, Maria Elena Avale
Article
Clinical Neurology
Daniel A. Solomon, Alan Stepto, Wing Hei Au, Yoshitsugu Adachi, Danielle C. Diaper, Rachel Hall, Anjeet Rekhi, Adel Boudi, Paraskevi Tziortzouda, Youn-Bok Lee, Bradley Smith, Jessika C. Bridi, Greta Spinelli, Jonah Dearlove, Dickon M. Humphrey, Jean-Marc Gallo, Claire Troakes, Manolis Fanto, Matthias Soller, Boris Rogelj, Richard B. Parsons, Christopher E. Shaw, Tibor Hortobagyi, Frank Hirth
Article
Multidisciplinary Sciences
Monika Hiller, Maria Sofia Falzarano, Iker Garcia-Jimenez, Valentina Sardone, Ruurd C. Verheul, Linda Popplewell, Karen Anthony, Estibaliz Ruiz-Del-Yerro, Hana Osman, Jelle J. Goeman, Kamel Mamchaoui, George Dickson, Alessandra Ferlini, Francesco Muntoni, Annemieke Aartsma-Rus, Virginia Arechavala-Gomeza, Nicole A. Datson, Pietro Spitali
Article
Neurosciences
Michael Naidoo, Karen Anthony
MOLECULAR NEUROBIOLOGY
(2020)
Article
Biochemistry & Molecular Biology
Youn-Bok Lee, Emma L. Scotter, Do-Young Lee, Claire Troakes, Jacqueline Mitchell, Boris Rogelj, Jean-Marc Gallo, Christopher E. Shaw
Summary: This study investigates the role of cytoplasmic TDP-43 in stress granule formation and response to stress, with findings suggesting that TDP-43 relocalizes to the cytoplasm through different mechanisms under different stress conditions. Additionally, the study demonstrates that relocalization of TDP-43 induces PARP cleavage, leading to cellular toxicity, and reveals changes in other cytoplasmic structures during stress recovery.
HUMAN MOLECULAR GENETICS
(2022)
Review
Biochemistry & Molecular Biology
Karen Anthony
Summary: This article reviews the common RNA-based drug modalities and their current and potential applications in neurological diseases. It highlights the rapid progress in rare genetic diseases and neurodegenerative disorders, but also the significant challenge of safe and effective delivery to the brain. It discusses the emergence of individualized RNA-based therapies for ultra-rare diseases and the potential application in more common conditions like Alzheimer's disease and stroke. The untapped potential in behavioral disorders and central nervous system tumors is also mentioned.
Article
Computer Science, Information Systems
Mahmood Khalsan, Lee R. Machado, Eman Salih Al-Shamery, Suraj Ajit, Karen Anthony, Mu Mu, Michael Opoku Agyeman
Summary: This article provides a comprehensive review of recent cancer studies that utilize gene expression data for cancer prediction, tumor identification, and stratification. It also discusses biomarker studies related to various cancer types. The article covers multiple aspects of machine learning in cancer research and highlights some technical issues.
Editorial Material
Multidisciplinary Sciences
Jean-Marc Gallo, Dieter Edbauer
Article
Biotechnology & Applied Microbiology
Karen Anthony, Pierpaolo Ala, Francesco Catapano, Jinhong Meng, Joana Domingos, Mark Perry, Valeria Ricotti, Kate Maresh, Lauren C. C. Phillips, Laurent Servais, Andreea M. M. Seferian, Silvana De Lucia, Imelda de Groot, Yvonne D. D. Krom, J. G. M. Verschuuren, Erik H. H. Niks, Volker Straub, Michela Guglieri, Thomas Voit, Jennifer Morgan, Francesco Muntoni
Summary: Duchenne muscular dystrophy (DMD) is a genetic disorder caused by the lack of dystrophin protein. Some patients with DMD have rare fibers that express dystrophin. The muscle pathology of DMD includes inflammation and immune cell infiltration. Strategies to restore dystrophin expression in DMD patients include exon skipping and gene therapy. However, restoring dystrophin may trigger T cell-mediated immune responses in patients, which can affect treatment efficacy and lead to adverse events. A study on pediatric boys with DMD found that approximately 8% of patients had pre-existing T cell-mediated immune responses to dystrophin, despite steroid treatment. This information is important for considering immunological baseline before clinical trials and future studies on DMD.
HUMAN GENE THERAPY
(2023)
Review
Oncology
Leanne Jones, Michael Naidoo, Lee R. Machado, Karen Anthony
Summary: Mutation of the DMD gene causes muscular dystrophies, but it is also implicated in the development of major cancer types. Disruption of the balance of DMD gene products in cancer may play a key role in tumorigenesis. Further study into the potential role of DMD gene products in cancer is needed to develop new therapeutics.