Article
Multidisciplinary Sciences
Chunxing Yang, Tao Qiao, Jia Yu, Hongyan Wang, Yansu Guo, Johnny Salameh, Jake Metterville, Sepideh Parsi, Issa Yusuf, Robert H. Brown, Huaibin Cai, Zuoshang Xu
Summary: Modestly increased expression of TDP-43 gene has been found to be associated with ALS and other neurological disorders. The establishment of a transgenic mouse model allows researchers to study the mechanisms of these diseases and provides insights for developing treatment methods.
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)
Article
Neurosciences
Nirma D. Perera, Doris Tomas, Nayomi Wanniarachchillage, Brittany Cuic, Sophia J. Luikinga, Valeria Rytova, Bradley J. Turner
Summary: Autophagy plays a crucial role in maintaining cell homeostasis, but excessive induction may accelerate neurodegenerative diseases. This study demonstrated that stimulating autophagy with rilmenidine exacerbated the ALS phenotype in a TDP-43 mouse model, likely through excessive mitochondrial clearance in motor neurons. Balancing autophagy stimulation and hyperactive mitophagy is essential in ALS and other neurodegenerative diseases.
NEUROBIOLOGY OF DISEASE
(2021)
Article
Biochemistry & Molecular Biology
Niharika Nag, Timir Tripathi
Summary: Nucleocytoplasmic transport is impaired in C9-ALS/FTLD, and a protein called FG-Nup62 is found to be mislocalized and colocalized with TDP-43, promoting its transition from liquid to solid state. This study highlights the involvement of Nup62 in the pathogenesis of ALS/FTLD and its interaction with TDP-43.
ACS CHEMICAL NEUROSCIENCE
(2022)
Review
Neurosciences
Sean S. Keating, Rebecca San Gil, Molly E. Swanson, Emma L. Scotter, Adam K. Walker
Summary: Our understanding of amyotrophic lateral sclerosis and frontotemporal dementia has greatly improved since the discovery of TAR DNA-binding protein 43 (TDP-43) inclusions as the key pathology. Recent studies have provided insights into the function of TDP-43 and its dysfunction in these neurodegenerative diseases. The formation and aggregation of pathological TDP-43 species contribute to cellular dysfunction and toxicity, and various protein homeostasis mechanisms play a role in combating TDP-43 aggregation and promoting disease progression. Future therapeutic strategies targeting TDP-43 clearance show promise in treating these diseases.
PROGRESS IN NEUROBIOLOGY
(2022)
Review
Cell Biology
Afshin Babazadeh, Stephanie L. Rayner, Albert Lee, Roger S. Chung
Summary: A common feature of adult-onset neurodegenerative diseases is the presence of specific pathological protein accumulations. Restoring protein homeostasis of these accumulations may represent a potential therapeutic strategy. This review discusses the mechanisms leading to disrupted protein homeostasis and explores small molecule-based therapies for modulating these mechanisms.
AGEING RESEARCH REVIEWS
(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
Hiroyuki Yabata, Yuichi Riku, Hiroaki Miyahara, Akio Akagi, Jun Sone, Makoto Urushitani, Mari Yoshida, Yasushi Iwasaki
Summary: The study aimed to evaluate the relationship between the expression level of nuclear TDP-43 and the pathological properties of cytoplasmic aggregates in ALS cases. The results showed that the maturation of cytoplasmic TDP-43 inclusions correlates with the depletion of nuclear TDP-43 in each affected neuron. This suggests that an imbalance between nuclear and cytoplasmic TDP-43 may be an essential pathway to TDP-43 pathology.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Cell Biology
Rachel Atkinson, Jacqueline Leung, James Bender, Matthew Kirkcaldie, James Vickers, Anna King
Summary: Mislocalization of TDP-43 protein in mouse retinal ganglion cells led to alterations in neurofilament expression and a decrease in neurofilament-positive axons in the optic nerve, accompanied by increased microglial density. Furthermore, TDP-43 mislocalization was associated with increased pre-synaptic input into retinal ganglion cells.
DISEASE MODELS & MECHANISMS
(2021)
Article
Biochemistry & Molecular Biology
Virginie Petel Legare, Christian J. Rampal, Tyler J. N. Gurberg, Ziyaan A. Harji, Xavier Allard-Chamard, Esteban C. Rodriguez, Gary A. B. Armstrong
Summary: This study utilized the CRISPR/Cas9 system and homology directed repair to introduce a myc epitope sequence into the zebrafish genome. The expressed tagged protein was successfully detected using western blot and immunofluorescence techniques. This methodology has important implications for zebrafish researchers and others interested in developing animal models with endogenously tagged proteins.
COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY B-BIOCHEMISTRY & MOLECULAR BIOLOGY
(2022)
Review
Neurosciences
Ariel Ionescu, Topaz Altman, Eran Perlson
Summary: Axon degeneration and NMJ disruption are crucial in ALS, but the mechanisms leading to these pathologies remain unclear. TDP-43 mislocalization and accumulation are common in ALS patients and have been observed in intramuscular nerves of early symptomatic patients. This suggests a gain of function for TDP-43 in axons, potentially contributing to early NMJ disruption. This review discusses the process of TDP-43 accumulation and phosphorylation in axons, its role in healthy axons, and possible mechanisms connecting TDP-43 pathology to axon and NMJ degeneration in ALS.
MOLECULAR NEURODEGENERATION
(2023)
Article
Neurosciences
Mukesh Gautam, Baris Genc, Benjamin Helmold, Angela Ahrens, Janis Kuka, Marina Makrecka-Kuka, Aksu Gunay, Nuran Kocak, Izaak R. Aguilar-Wickings, Dennis Keefe, Guozhu Zheng, Suchitra Swaminathan, Martin Redmon, Hatim A. Zariwala, P. Hande Ozdinler
Summary: Mitochondrial defects are a common cause of neuronal vulnerability in neurodegenerative diseases, and TDP-43 pathology is frequently observed. By using a mouse model of ALS, researchers found that SBT-272, a small molecule that stabilizes cardiolipin in the inner mitochondrial membrane, improved mitochondrial structure and function in diseased upper motor neurons. Chronic treatment with SBT-272 also reduced astrogliosis, microgliosis, and TDP-43 pathology in the ALS motor cortex. These findings highlight the therapeutic potential of SBT-272 in the context of TDP-43 pathology and mitochondrial dysfunction.
NEUROBIOLOGY OF DISEASE
(2023)
Article
Neurosciences
Marcus S. Dyer, Adele Woodhouse, Catherine A. Blizzard
Summary: ALS is characterized by the destruction of upper- and lower motor neurons, with the mislocalization of TDP-43 protein potentially causing hyperexcitability of upper motor neurons in ALS patients. TDP-43 mislocalization is found to impact the formation and durability of excitatory synapses, leading to network dysfunction in ALS.
Article
Neurosciences
Marcus S. Dyer, G. Lorenzo Odierna, Rosemary M. Clark, Adele Woodhouse, Catherine A. Blizzard
Summary: This study investigates the relationship between cortical hyperexcitability and altered synaptic input in amyotrophic lateral sclerosis (ALS) using a mouse model. The findings suggest that intrinsic hyperexcitability precedes changes to excitatory synaptic connections, highlighting the significance of hyperexcitability as a primary mechanism of ALS and re-contextualizing synaptic changes as secondary adaptive responses.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2023)
Article
Neurosciences
Erik M. Lehmkuhl, Suvithanandhini Loganathan, Eric Alsop, Alexander D. Blythe, Tina Kovalik, Nicholas P. Mortimore, Dianne Barrameda, Chuol Kueth, Randall J. Eck, Bhavani B. Siddegowda, Archi Joardar, Hannah Ball, Maria E. Macias, Robert Bowser, Kendall Van Keuren-Jensen, Daniela C. Zarnescu
Summary: ALS is a genetically heterogeneous neurodegenerative disease characterized by cytoplasmic aggregates containing TDP-43. Using Drosophila models, it was found that TDP-43 proteinopathy affects translational alterations in motor neurons, particularly impacting spliceosome, pentose phosphate, and oxidative phosphorylation pathways. The study also identified Dlp/GPC6 as a novel target of TDP-43 proteinopathy.
ACTA NEUROPATHOLOGICA COMMUNICATIONS
(2021)
Correction
Multidisciplinary Sciences
Benoit Briard, Thierry Fontaine, Parimal Samir, David E. Place, Laetitia Muszkieta, R. K. Subbarao Malireddi, Rajendra Karki, Shelbi Christgen, Perrine Bomme, Peter Vogel, Remi Beau, Emilia Mellado, Oumaima Ibrahim-Granet, Bernard Henrissat, Ravi C. Kalathur, Cam Robinson, Jean-Paul Latge, Thirumala-Devi Kanneganti
Article
Multidisciplinary Sciences
David E. Place, R. K. Subbarao Malireddi, Jieun Kim, Peter Vogel, Masahiro Yamamoto, Thirumala-Devi Kanneganti
Summary: This study reveals that IFN and IFN-induced guanylate-binding proteins play important roles in regulating bone immunology, contributing to limiting inflammatory and age-associated bone loss.
NATURE COMMUNICATIONS
(2021)
Article
Oncology
Sarang Tartey, Geoffrey Neale, Peter Vogel, R. K. Subbarao Malireddi, Thirumala-Devi Kanneganti
Summary: Macrophages play critical roles in tissue homeostasis, cell proliferation, and tumor metastasis. Tumor-associated macrophages (TAM) are known for their immunosuppressive functions in solid tumors, with MYD88 playing a key role in tumor progression. Targeting the MYD88/IL1 receptor axis could potentially enhance anti-tumor effects in a variety of cancers through regulating immune responses.
Article
Hematology
Meghan E. Turnis, Ewa Kaminska, Kaitlyn H. Smith, Brittany J. Kartchner, Peter Vogel, Jonathan D. Laxton, Richard A. Ashmun, Paul A. Ney, Joseph T. Opferman
Summary: Deletion of erythroid-specific Mcl1 results in embryonic lethality due to severe anemia caused by lack of mature red blood cells. MCL-1 is required only during early definitive erythropoiesis, with developing erythrocytes becoming MCL-1 independent and upregulating BCL-xL expression during later stages.
Article
Oncology
Lee-Ann Van de Velde, E. Kaitlynn Allen, Jeremy Chase Crawford, Taylor L. Wilson, Clifford S. Guy, Marion Russier, Leonie Zeitler, Armita Bahrami, David Finkelstein, Stephane Pelletier, Stacey Schultz-Cherry, Paul G. Thomas, Peter J. Murray
Summary: This study investigated the role of immune cells in tumor formation using a neuroblastoma model, and found that CD4(+) T cells and macrophages play significant roles in the process of tumor formation.
Article
Virology
Yi Xue, Dong Yang, Peter Vogel, Jennifer Stabenow, Lillian Zalduondo, Ying Kong, Yazhini Ravi, Chittoor B. Sai-Sudhakar, Jyothi Parvathareddy, Ernestine Hayes, Shannon Taylor, Elizabeth Fitzpatrick, Colleen B. Jonsson
Summary: The Syrian hamster has been proven to be a useful model for evaluating the treatment and vaccines of SARS-CoV-2. The evaluation of lung histopathology scores at 4 dpi and 8 dpi showed that these time points are prime indicators for assessing moderate lung pathology, including bronchial hyperplasia, alveolar involvement, and bronchiolization. Furthermore, early infection in the hamsters led to increased neutrophil levels, red blood cell count, and hematocrit. The examination also revealed severe damage to the pulmonary vasculature, suggesting endothelialitis as a possible determinant of the pathological findings along with the host inflammatory response. In addition, the pathological examination of the heart showed evidence of intracardiac platelet/fibrin aggregates, indicating a hypercoagulative state in the infected hamsters.
Article
Immunology
Brianna L. Bullard, Jennifer DeBeauchamp, Matthew J. Pekarek, Erika Petro-Turnquist, Peter Vogel, Richard J. Webby, Eric A. Weaver
Summary: There is a critical need for an improved H3N2 influenza virus vaccine due to low efficacy rates and increased morbidity and mortality associated with H3N2-dominated influenza seasons. In this study, a computational design strategy was used to create epitope-optimized, broadly cross-reactive H3 hemagglutinins for a universal H3N2 influenza vaccine. The results showed that the Epigraph vaccine induced stronger cross-reactive antibody responses and T-cell immunity compared to the traditional egg-based vaccine, providing higher protection against a wide range of H3N2 strains.
Letter
Oncology
Fabienne R. S. Adriaanse, Jennifer L. Kamens, Peter Vogel, Sadie M. Sakurada, Shondra M. Pruett-Miller, Ronald W. Stam, C. Michel Zwaan, Tanja A. Gruber
Article
Genetics & Heredity
Eric P. Rahrmann, David Shorthouse, Amir Jassim, Linda P. Hu, Mariaestela Ortiz, Betania Mahler-Araujo, Peter Vogel, Marta Paez-Ribes, Atefeh Fatemi, Gregory J. Hannon, Radhika Iyer, Jay A. Blundon, Filipe C. Lourenco, Jonathan Kay, Rosalynn M. Nazarian, Benjamin A. Hall, Stanislav S. Zakharenko, Douglas J. Winton, Liqin Zhu, Richard J. Gilbertson
Summary: The ion channel NALCN has been identified as a key regulator of cancer metastasis and nonmalignant cell dissemination, even in the absence of oncogenic mutations, allowing normal structures to form at secondary sites. This finding uncovers a potential new target for antimetastatic therapies.
Article
Multidisciplinary Sciences
Diego A. Rodriguez, Giovanni Quarato, Swantje Liedmann, Bart Tummers, Ting Zhang, Cliff Guy, Jeremy Chase Crawford, Gustavo Palacios, Stephane Pelletier, Halime Kalkavan, Jeremy J. P. Shaw, Patrick Fitzgerald, Mark J. Chen, Siddharth Balachandran, Douglas R. Green
Summary: This study identifies a molecular mechanism whereby Caspase-8 and FADD suppress spontaneous necroptotic cell death. The absence of Caspase-8 or FADD leads to the activation of RIPK3 and MLKL, resulting in necroptosis. This process relies on the nucleic acid sensor ZBP1 and its associated signaling pathways.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Pathology
Jerrold M. Ward, Peter Vogel, John P. Sundberg
Summary: This study describes the histopathological findings of brain and spinal cord in 20-month-old mice from 28 inbred Jackson Laboratory mouse strains. Common lesions include axonal dystrophy in the sensory tract of the dorsal medulla and mineralization in the thalamus. Most strains showed evidence of impairment of the ubiquitin-proteasome system and/or suspected autophagy.
VETERINARY PATHOLOGY
(2022)
Article
Endocrinology & Metabolism
Annelise Cassidy, Melda Onal, Stephane Pelletier
Summary: Genetically modified mouse models have greatly contributed to our understanding of biological systems. Recent advances in genome editing technologies have made it easier and more precise to manipulate the mouse genome.
Article
Multidisciplinary Sciences
Lalita Mazgaeen, Matthew Yorek, Saurabh Saini, Peter Vogel, David K. Meyerholz, Thirumala-Devi Kanneganti, Prajwal Gurung
Summary: Mice with a specific amino acid substitution in SHP1 protein (Ptpn6(spin) mice) develop an autoinflammatory disease. When Ptpn6(spin) bone marrow cells are transferred into Cd47-deficient mice, marked weight loss and death occur. The study suggests that gut leakage caused by pathogenic neutrophils may contribute to the morbidity and mortality in Cd47(-/-) mice receiving Ptpn6(spin) cells. IL-1 blockade with anakinra can rescue the disease phenotype.
Article
Multidisciplinary Sciences
Annelise M. Cassidy, Destinee B. Thomas, Emin Kuliyev, Hanying Chen, Stephane Pelletier
Summary: A recent study successfully applied artificial introns to engineer conditional alleles in mice, showing a promising approach for generating conditional alleles in mice.
Article
Biochemical Research Methods
Annelise Cassidy, Stephane Pelletier
Summary: In this article, the generation of conditional alleles in mice using the DECAI approach is described. The steps for CRISPR-mediated insertion of the short DECAI cassette within exon 3 of Scyl1 and the validation of alleles at genomic, transcriptomic, and protein levels are detailed. This strategy simplifies the process of generating mice with conditional alleles.