Article
Multidisciplinary Sciences
Macy L. Sprunger, Ken Lee, Brian S. Sohn, Meredith E. Jackrel
Summary: We developed a yeast model of MATR3 proteotoxicity and aggregation, and found that MATR3 is toxic and forms nuclear condensates in yeast. Disease-associated mutations impair condensate dynamics and morphology. Hsp104 variants can reverse aberrant phase separation of various RBPs and counter MATR3 toxicity. Our yeast model can be used to screen for modulators of MATR3 misfolding.
Review
Medicine, Research & Experimental
Ahmed M. Malik, Sami J. Barmada
Summary: RNA-binding proteins (RBPs) are essential for the physiological function of neurons, muscle, and other tissue types, and MATR3 is a poorly understood RBP implicated in neurodegenerative diseases and myopathy. Studying its functions, regulation, and pathogenesis could provide insights for treating these diseases.
Article
Biochemistry & Molecular Biology
Shanez Haouari, Christian Robert Andres, Debora Lanznaster, Sylviane Marouillat, Celine Brulard, Audrey Dangoumau, Devina Ung, Charlotte Veyrat-Durebex, Frederic Laumonnier, Helene Blasco, Philippe Couratier, Philippe Corcia, Patrick Vourc'h
Summary: Using next-generation sequencing, pathogenic variants in genes of the ubiquitin pathway were identified in ALS patients, including known genes FUS, CCNF, and UBQLN2, as well as new genes such as HECW1. Overexpression of NEDL1, a protein encoded by HECW1, was found to be associated with increased cell death and mislocalization of TDP-43. These findings provide further evidence for the involvement of the ubiquitin pathway in ALS and suggest the need for further investigation of the HECW1 gene and NEDL1 in ALS pathophysiology.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Cell Biology
Chaohua Cong, Weiwei Liang, Chunting Zhang, Ying Wang, Yueqing Yang, Xudong Wang, Shuyu Wang, Di Huo, Hongyong Wang, Di Wang, Honglin Feng
Summary: In ALS models, the expression and activation of PAK4 significantly decreased as the disease progressed due to the negative regulation of miR-9-5p. Silencing PAK4 increased apoptosis of motor neurons by inhibiting CREB-mediated neuroprotection, while overexpression of PAK4 protected motor neurons from degeneration by activating CREB signaling.
CELL PROLIFERATION
(2021)
Review
Clinical Neurology
Luqing Yao, Xiaoyan He, Baolong Cui, Fang Zhao, Chang Zhou
Summary: NEK1 mutations were identified as a cause of ALS, with LoF and missense mutations associated with increased risk. The frequency of LoF mutations was higher in European patients, indicating a potential genetic predisposition difference between Asian and European populations.
NEUROLOGICAL SCIENCES
(2021)
Article
Neurosciences
Miguel Oliveira Santos, Marta Gromicho, Ana Pronto-Laborinho, Mamede de Carvalho
Summary: Amyotrophic lateral sclerosis (ALS) and myopathy are part of a genetic syndrome called multisystem proteinopathy. They can occur together or separately, and may be associated with other clinical features. This study aims to characterize three sporadic ALS patients, one with concurrent myopathy and two with previous myopathy diagnoses before motor neuron signs emerged. These cases suggest a potential connection between skeletal muscle degeneration and motor neuron damage.
Article
Neurosciences
Guangnan Peng, Ao Gu, Hongyan Niu, Linlin Chen, Yan Chen, Miaojin Zhou, Yiti Zhang, Jie Liu, Licong Cai, Desheng Liang, Xionghao Liu, Mujun Liu
Summary: UBQLN2 colocalizes with SG component proteins G3BP1, TIA-1, ATXN2, and PABPC1, participating in regulating SG dynamics. UBQLN2 mutation affects stress granule assembly by regulating TIA-1. Moreover, overexpression of UBQLN2 P497H mutant inhibits 4E-BP1 phosphorylation and affects TDP-43's nuclear and cytoplasmic distribution.
CNS NEUROSCIENCE & THERAPEUTICS
(2022)
Review
Chemistry, Medicinal
Mohamed F. Elmansy, Cory T. Reidl, Mizzanoor Rahaman, P. Hande Ozdinler, Richard B. Silverman
Summary: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that affects the motor neurons in the brain and spinal cord. Despite the approval of three drugs, there is still a need for better treatment strategies. Various approaches, including targeting genetic mutations and reducing oxidative stress, have been explored. Additionally, repurposing previously identified drugs has also been studied. This review discusses drug discovery efforts targeting cellular pathologies caused by genetic mutations in ALS and offers recommendations for more effective ALS drug discovery.
MEDICINAL RESEARCH REVIEWS
(2023)
Article
Environmental Sciences
Marina Tesauro, Maurizio Bruschi, Tommaso Filippini, Sandra D'Alfonso, Letizia Mazzini, Lucia Corrado, Michela Consonni, Marco Vinceti, Paola Fusi, Chiara Urani
Summary: ALS is a progressive neurodegenerative disorder that may be related to genetic or environmental factors. Controversial findings exist regarding the role of environmental factors in ALS cases.
ENVIRONMENTAL RESEARCH
(2021)
Article
Clinical Neurology
Jing Ma, Xiaomin Pang, Shan Huang, Jing Zhang, Juan Wang, Rongjuan Zhao, Xueli Chang, Junhong Guo, Wei Zhang
Summary: The study aimed to investigate genetic characteristics in Chinese patients with familial or young-onset ALS, identifying two novel mutations. Patients with familial or young-onset ALS often carried related gene mutations, suggesting routine genetic sequencing should be performed.
NEUROLOGICAL SCIENCES
(2022)
Article
Clinical Neurology
Philippe Corcia, Pascal Lejeune, Patrick Vourc'h, Stephane Beltran, Anne-Sophie Piegay, Helene Blasco, Vincent Meininger
Summary: This study characterized the prototypical phenotype of patients with amyotrophic lateral sclerosis (ALS) associated with PFN1 mutations and identified clinical indications for testing mutations in this gene. The main clinical findings for familial ALS linked to PFN1 were identified as pedigrees with over five cases, an onset age around 50 years, onset in the lower limbs, and the absence of cognitive impairment. The similarities with other ALS mutations prompt a review of ALS classifications based on both phenotype and genotype.
EUROPEAN JOURNAL OF NEUROLOGY
(2023)
Article
Biochemistry & Molecular Biology
Venkatesan Santhanam, Priya Modi, Umesh K. Mishra, Ishrat Jahan, Namakkal G. Ramesh, Shashank Deep
Summary: In this study, the first iminosugar that inhibits superoxide dismutase fibrillation associated with ALS is reported. Novel triazole and tetrazole embedded iminosugars were successfully synthesized, and one of these designed iminosugars was found to inhibit SOD1 fibrillation and break pre-formed fibrils. Docking and MD simulation studies indicated that this compound interacts with the key residue Arg69 of SOD1 through hydrogen bonding.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2023)
Review
Clinical Neurology
Thomas H. Julian, Sarah Boddy, Mahjabin Islam, Julian Kurz, Katherine J. Whittaker, Tobias Moll, Calum Harvey, Sai Zhang, Michael P. Snyder, Christopher McDermott, Johnathan Cooper-Knock, Pamela J. Shaw
Summary: Mendelian randomization studies on amyotrophic lateral sclerosis show a causal link between blood lipids and the disease risk, while factors like smoking and immune function require further investigation for confirmation. The use of high methodological standards and replication across different datasets are essential for reliable results in Mendelian randomization studies.
Article
Geriatrics & Gerontology
Sheng Chen, Rui-Ling Zhou, Wei Zhang, Chun-Hui Che, Shu-Yan Feng, Hua-Pin Huang, Chang-Yun Liu, Zhang-Yu Zou
Summary: TARDBP mutations are common in both FALS and SALS in China, leading to a wide spectrum of diseases including ALS, FTD, and parkinsonism. The identification of a previously unreported mutation highlights the importance of including the TARDBP gene in genetic screening for related diseases.
NEUROBIOLOGY OF AGING
(2021)
Review
Medicine, General & Internal
Can Cui, Jiangwei Sun, Kyla A. McKay, Caroline Ingre, Fang Fang
Summary: This systematic review investigated the association between medication use and ALS risk, and found no strong evidence linking any medication use with the risk of ALS.
Article
Genetics & Heredity
James D. Thomas, Jacob T. Polaski, Qing Feng, Emma J. De Neef, Emma R. Hoppe, Maria V. McSharry, Joseph Pangallo, Austin M. Gabel, Andrea E. Belleville, Jacqueline Watson, Naomi T. Nkinsi, Alice H. Berger, Robert K. Bradley
Article
Multidisciplinary Sciences
Moyi Li, Yan Zhuang, Ranjan Batra, James D. Thomas, Mao Li, Curtis A. Nutter, Marina M. Scotti, Helmut A. Carter, Zhan Jun Wang, Xu-Sheng Huang, Chuan Qiang Pu, Maurice S. Swanson, Wei Xie
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2020)
Article
Biochemistry & Molecular Biology
Kristen Skruber, Peyton Warp, Rachael Shklyarov, James D. Thomas, Maurice S. Swanson, Jessica L. Henty-Ridilla, Tracy-Ann Read, Eric A. Vitriol
Article
Multidisciplinary Sciences
Lukasz J. Sznajder, Marina M. Scotti, Jihae Shin, Katarzyna Taylor, Franjo Ivankovic, Curtis A. Nutter, Faaiq N. Aslam, S. H. Subramony, Laura P. W. Ranum, Maurice S. Swanson
NATURE COMMUNICATIONS
(2020)
Article
Engineering, Biomedical
Ranjan Batra, David A. Nelles, Daniela M. Roth, Florian Krach, Curtis A. Nutter, Takahiro Tadokoro, James D. Thomas, Lukasz J. Sznajder, Steven M. Blue, Haydee L. Gutierrez, Patrick Liu, Stefan Aigner, Oleksandr Platoshyn, Atsushi Miyanohara, Martin Marsala, Maurice S. Swanson, Gene W. Yeo
Summary: The study demonstrates that CRISPR-mediated RNA targeting can sustainably reverse molecular and physiological phenotypes in mouse models of myotonic dystrophy type I, offering a new strategy for treating DM1 and other MRE-related diseases.
NATURE BIOMEDICAL ENGINEERING
(2021)
Article
Biochemistry & Molecular Biology
Jodi L. Bubenik, Melissa Hale, Ona McConnell, Eric T. Wang, Maurice S. Swanson, Robert C. Spitale, J. Andrew Berglund
Summary: In vivo RNA structure analysis has evolved into a powerful tool through enrichment of low abundance targets for improved analysis of low abundance transcripts, allowing for studying autoregulated events in pre-mRNA in a cellular context.
Article
Biochemistry & Molecular Biology
Sydney X. Lu, Emma De Neef, James D. Thomas, Erich Sabio, Benoit Rousseau, Mathieu Gigoux, David A. Knorr, Benjamin Greenbaum, Yuval Elhanati, Simon J. Hogg, Andrew Chow, Arnab Ghosh, Abigail Xie, Dmitriy Zamarin, Daniel Cui, Caroline Erickson, Michael Singer, Hana Cho, Eric Wang, Bin Lu, Benjamin H. Durham, Harshal Shah, Diego Chowell, Austin M. Gabel, Yudao Shen, Jing Liu, Jian Jin, Matthew C. Rhodes, Richard E. Taylor, Henrik Molina, Jedd D. Wolchok, Taha Merghoub, Luis A. Diaz, Omar Abdel-Wahab, Robert K. Bradley
Summary: The study demonstrates that modulation of splicing through specific drug classes generates genuine neoantigens and enhances anti-tumor immunity, augmenting checkpoint immunotherapy.
Article
Multidisciplinary Sciences
Athea Vichas, Amanda K. Riley, Naomi T. Nkinsi, Shriya Kamlapurkar, Phoebe C. R. Parrish, April Lo, Fujiko Duke, Jennifer Chen, Iris Fung, Jacqueline Watson, Matthew Rees, Austin M. Gabel, James D. Thomas, Robert K. Bradley, John K. Lee, Emily M. Hatch, Marina K. Baine, Natasha Rekhtman, Marc Ladanyi, Federica Piccioni, Alice H. Berger
Summary: CRISPR-based cancer dependency maps have revealed unique vulnerabilities of RIT1-mutant lung cancer cells, particularly to loss of spindle assembly checkpoint regulators, synergies with YAP1, and increased sensitivity to Aurora A inhibitors. These findings suggest potential therapeutic targets for RIT1-mutant lung cancer in the RAS pathway, spindle assembly checkpoint, and Hippo/YAP1 network.
NATURE COMMUNICATIONS
(2021)
Article
Cell Biology
Phoebe C. R. Parrish, James D. Thomas, Austin M. Gabel, Shriya Kamlapurkar, Robert K. Bradley, Alice H. Berger
Summary: The use of pgPEN method has led to the discovery of important cancer vulnerabilities and synthetic lethal paralog pairs, which can potentially guide the selection of drug targets and provide insights into genetic interactions in cancer.
Article
Biology
Silvie Franck, Edouard Couvreu De Deckersberg, Jodi L. Bubenik, Christina Markouli, Lise Barbe, Joke Allemeersch, Pierre Hilven, Geoffrey Duque, Maurice S. Swanson, Alexander Gheldof, Claudia Spits, Karen D. Sermon
Summary: This study compared the differentiation potential of DM1 cells and healthy cells in myogenesis using a comprehensive multi-omics approach. The findings showed abnormal myogenesis in DM1 cells, including altered myotube generation. Additionally, aberrant inflammatory response, increased CpG methylation, and RNA mis-splicing were observed in DM1 cells during differentiation.
Article
Biochemistry & Molecular Biology
Thomas Spruce, Mireya Plass, Andre Gohr, Debashish Ray, Maria Martinez de Lagran, Gregor Rot, Ana Novoa, Demian Burguera, Jon Permanyer, Marta Miret, Hong Zheng, Maurice S. Swanson, Quaid Morris, Moises Mallo, Mara Dierssen, Timothy R. Hughes, Barbara Pernaute, Manuel Irimia
Summary: Understanding the regulatory interactions that control gene expression during the development of novel tissues is a key goal of evolutionary developmental biology. Here, we show that Mbnl3 has evolved a novel placental function in eutherian mammals as a result of evolutionary specialization. Mbnl3 loss leads to increased placental growth and fetal resource allocation under limiting conditions.
Article
Cell Biology
Mingyi Xie, Maurice S. Swanson
GENES & DEVELOPMENT
(2020)