Review
Neurosciences
Santiago Mora, Ilary Allodi
Summary: Action selection is a crucial aspect of cognition that guides behavior, from motor patterns to executive functions. It relies on complex neural circuits and connective loops within the brain and spinal cord. ALS and FTD, both neurodegenerative disorders, share disease etiology and pathophysiology, leading to the impairment of motor commands and executive functions. New evidence based on studies performed on animal models, post-mortem tissue, and patient derived stem cells supports the pathological loss of connectivity and selective impairment of neural circuits in ALS and FTD.
FRONTIERS IN NEURAL CIRCUITS
(2023)
Article
Clinical Neurology
Robert David Henderson, Kasper Planeta Kepp, Andrew Eisen
Summary: Amyotrophic lateral sclerosis and frontotemporal dementia are neurodegenerative diseases with complex cellular pathology. The paper emphasizes the importance of evolution in the development of higher cortical function and the impact of factors related to increased lifespan on neuronal function.
FRONTIERS IN NEUROLOGY
(2022)
Editorial Material
Biochemistry & Molecular Biology
Natalia B. Nedelsky, J. Paul Taylor
Summary: Genetics of human disease plays a crucial role in understanding cellular processes and vulnerabilities associated with dysfunction. The genetics of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have revealed the role of biomolecular condensation in organizing cellular contents and its link to neurodegeneration.
Review
Neurosciences
Alexander Schmitz, Joao Pinheiro Marques, Irina Oertig, Niran Maharjan, Smita Saxena
Summary: The most common genetic cause of ALS and FTD is a hexanucleotide expansion in the C9ORF72 gene, which leads to various disease pathologies. Different forms of DPRs have different contributions to disease pathology, and recent advances in neuropathology and cellular studies have provided clues to understand their effects better.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2021)
Review
Neurosciences
Puja R. Mehta, Anna-Leigh Brown, Michael E. Ward, Pietro Fratta
Summary: TDP-43 is an RNA-binding protein that plays a crucial role in nuclear splicing. It is implicated in various neurodegenerative disorders, with its mislocalization from the nucleus to the cytoplasm. TDP-43 proteinopathy encompasses a range of incurable neurodegenerative diseases, and the discovery of cryptic exons holds potential for diagnostics and therapeutics.
MOLECULAR NEURODEGENERATION
(2023)
Article
Neurosciences
Lizhu Xu, Dan Wang, Lu Zhao, Zhengsheng Yang, Xu Liu, Xinyue Li, Tingli Yuan, Ye Wang, Tianzhuang Huang, Ning Bian, Yuqun He, Xinglong Chen, Baohong Tian, Zexian Liu, Fucheng Luo, Wei Si, Guangping Gao, Weizhi Ji, Yuyu Niu, Jingkuan Wei
Summary: This study demonstrates that the Poly(PR) protein, resulting from the expanded G4C2 repeats in the C9orf72 gene, can independently induce neurodegeneration associated with C9-ALS/FTD, providing new insights into the pathogenesis of these diseases.
NEUROBIOLOGY OF DISEASE
(2023)
Article
Cell Biology
Hyun Sung, Thomas E. Lloyd
Summary: Macroautophagy is crucial for eliminating protein aggregates and damaged organelles, and its dysregulation is implicated in neurodegenerative diseases like ALS and FTD. The expansion of G4C2 repeats in the C9orf72 gene disrupts autophagosome formation, highlighting the importance of dynamic ER tubules.
Article
Multidisciplinary Sciences
Junhao Li, Manoj K. Jaiswal, Jo-Fan Chien, Alexey Kozlenkov, Jinyoung Jung, Ping Zhou, Mahammad Gardashli, Luc J. Pregent, Erica Engelberg-Cook, Dennis W. Dickson, Veronique V. Belzil, Eran A. Mukamel, Stella Dracheva
Summary: The repeat expansion in the C9orf72 gene is a common genetic cause of ALS and FTD. The study found pervasive alterations in gene expression and chromatin accessibility in neurons and astrocytes of C9-ALS patients, as well as gene expression changes in glial cells of C9-FTD patients. These findings indicate unique molecular disruptions in different cell types, brain regions, and diseases.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Krishnashish Bose, Arijit Maity, Khac Huy Ngo, J. Jeya Vandana, Neil A. Shneider, Anh Tuan Phan
Summary: This study visualizes the formation of higher-order structures by the G4C2 hexanucleotide repeat in the gene C9orf72, which is associated with amyotrophic lateral sclerosis and frontotemporal dementia. The researchers observed left-handed undulating G-wires with a periodicity of 4.4 nm and a uniform height in physiologically relevant conditions. These structures were resistant to degradation and could potentially accumulate in cells.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2022)
Article
Neurosciences
Cristian Arredondo, Carolina Cefaliello, Agnieszka Dyrda, Nur Jury, Pablo Martinez, Ivan Diaz, Armando Amaro, Helene Tran, Danna Morales, Maria Pertusa, Lorelei Stoica, Elsa Fritz, Daniela Corvalan, Sebastian Abarzua, Maxs Mendez-Ruette, Paola Fernandez, Fabiola Rojas, Meenakshi Sundaram Kumar, Rodrigo Aguilar, Sandra Almeida, Alexandra Weiss, Fernando J. Bustos, Fernando Gonzalez-Nilo, Carolina Otero, Maria Florencia Tevy, Daryl A. Bosco, Juan C. Saez, Thilo Kahne, Fen-Biao Gao, James D. Berry, Katharine Nicholson, Miguel Sena-Esteves, Rodolfo Madrid, Diego Varela, Martin Montecino, Robert H. Brown, Brigitte van Zundert
Summary: Non-cell-autonomous mechanisms, specifically the release of unidentified toxic factors by astrocytes, contribute to the neurodegenerative diseases ALS and FTD. Studies found that astrocytes with ALS/FTD-related mutations display elevated levels of intracellular inorganic polyphosphate (polyP), which is also present in astrocyte-conditioned media (ACM). Degradation or neutralization of polyP in ALS/FTD astrocytes or ACM prevents the death of motoneurons. Additionally, polyP staining signals are enriched in postmortem ALS spinal cord sections and ALS cerebrospinal fluid (CSF) exhibits increased concentrations of polyP, suggesting polyP as a potential therapeutic target and biomarker for ALS/FTD.
Article
Neurosciences
Mhoriam Ahmed, Charlotte Spicer, Jasmine Harley, J. Paul Taylor, Michael Hanna, Rickie Patani, Linda Greensmith
Summary: ALS and FTD are part of a disease spectrum with common pathological features and genetic causes. Disruption to protein homeostasis is a key feature of both conditions. Targeting the heat shock response (HSR) may have therapeutic potential for the treatment of ALS and FTD.
MOLECULAR NEUROBIOLOGY
(2023)
Article
Cell Biology
Hayley Robinson, Sk Imran Ali, Martha Elena Diaz-Hernandez, Rodrigo Lopez-Gonzalez
Summary: The G4C2 repeat expansion in C9ORF72 gene is the most common genetic cause of ALS and FTD. This study found an age-dependent decrease in telomere length in neurons from C9ORF72 carriers, along with dysregulation in the protein levels of shelterin complex members TRF2 and POT1.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Multidisciplinary Sciences
Ryota Hikiami, Toshifumi Morimura, Takashi Ayaki, Tomoyuki Tsukiyama, Naoko Morimura, Makiko Kusui, Hideki Wada, Sumio Minamiyama, Akemi Shodai, Megumi Asada-Utsugi, Shin-ichi Muramatsu, Takatoshi Ueki, Ryosuke Takahashi, Makoto Urushitani
Summary: This study reveals the molecular basis of ALS caused by FUS gene mutations, and identifies DHX30 as a key molecule in ALS-FUS. Mutant FUS results in mislocalization of DHX30 and promotes the colocalization of cytosolic FUS aggregates and stress granules. Mutant FUS disrupts the conformation of DHX30, leading to impaired mitochondrial translation and aggregate formation. This study is of great importance in understanding the pathogenesis of ALS.
SCIENTIFIC REPORTS
(2022)
Article
Multidisciplinary Sciences
Yoshifumi Sonobe, Jihad Aburas, Gopinath Krishnan, Andrew C. Fleming, Ghanashyam Ghadge, Priota Islam, Eleanor C. Warren, Yuanzheng Gu, Mark W. Kankel, Andre E. X. Brown, Evangelos Kiskinis, Tania F. Gendron, Fen-Biao Gao, Raymond P. Roos, Paschalis Kratsios
Summary: A C. elegans model of C9orf72-mediated ALS/FTD was generated, demonstrating the role of translation initiation factor eIF2D in regulating dipeptide repeat protein expression. Loss-of-function mutations in eIF2D reduce DPR levels and increase lifespan in the models, indicating a conserved mechanism in DPR expression.
NATURE COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Robin Waegaert, Sylvie Dirrig-Grosch, Haoyi Liu, Marion Boutry, Ping Luan, Jean-Philippe Loeffler, Frederique Rene
Summary: CHMP2B is a crucial protein involved in membrane scission events and its mutations are a rare cause of ALS and FTD. This study demonstrates that neuron-specific expression of the CHMP2B(intron5) mutant leads to progressive gait impairment and changes in the neuromuscular junction, similar to those observed in ALS patients.
Article
Surgery
Kanishka Mohib, Aravind Cherukuri, Yu Zhou, Qing Ding, Simon C. Watkins, David M. Rothstein
AMERICAN JOURNAL OF TRANSPLANTATION
(2020)
Article
Cell Biology
Jie Han, Leslie A. Goldstein, Wen Hou, Simon C. Watkins, Hannah Rabinowich
Summary: The study reveals that the non-apoptotic activity of endosomal CASP9 promotes the retrograde transport of IGF2R and is involved in endosomal sorting and lysosomal biogenesis. CASP9 deficiency leads to missorting of proteins, accumulation of late endosomes, and disruption of protein degradation. The findings suggest a novel cell survival function for CASP9 at the endosomal membrane.
Correction
Biochemistry & Molecular Biology
Jonathan Barroso-Gonzalez, Laura Garcia-Exposito, Song My Hoang, Michelle L. Lynskey, Justin L. Roncaioli, Arundhati Ghosh, Callen T. Wallace, Marco de Vitis, Mauro Modesti, Kara A. Bernstein, Saumendra N. Sarkar, Simon C. Watkins, Roderick J. O'Sullivan
Article
Multidisciplinary Sciences
Rogan A. Grant, Luisa Morales-Nebreda, Nikolay S. Markov, Suchitra Swaminathan, Melissa Querrey, Estefany R. Guzman, Darryl A. Abbott, Helen K. Donnelly, Alvaro Donayre, Isaac A. Goldberg, Zasu M. Klug, Nicole Borkowski, Ziyan Lu, Hermon Kihshen, Yuliya Politanska, Lango Sichizya, Mengjia Kang, Ali Shilatifard, Chao Qi, Jon W. Lomasney, A. Christine Argento, Jacqueline M. Kruser, Elizabeth S. Malsin, Chiagozie O. Pickens, Sean B. Smith, James M. Walter, Anna E. Pawlowski, Daniel Schneider, Prasanth Nannapaneni, Hiam Abdala-Valencia, Ankit Bharat, Cara J. Gottardi, G. R. Scott Budinger, Alexander Misharin, Benjamin D. Singer, Richard G. Wunderink
Summary: The study found that patients infected with SARS-CoV-2 have enriched T cells and monocytes in the alveolar space, suggesting that the virus infects alveolar macrophages and induces T cell production of interferon-, leading to inflammation and persistent alveolitis.
Article
Cell Biology
Alice Migazzi, Chiara Scaramuzzino, Eric N. Anderson, Debasmita Tripathy, Ivo H. Hernandez, Rogan A. Grant, Michela Roccuzzo, Laura Tosatto, Amandine Virlogeux, Chiara Zuccato, Andrea Caricasole, Tamara Ratovitski, Christopher A. Ross, Udai B. Pandey, Jose J. Lucas, Frederic Saudou, Maria Pennuto, Manuela Basso
Summary: Arginine methylation plays a crucial role in regulating the vesicular transport of huntingtin protein along the axon, and increasing HTT methylation could be a potential therapeutic target for Huntington's disease.
Article
Critical Care Medicine
Chiagozie O. Pickens, Catherine A. Gao, Michael J. Cuttica, Sean B. Smith, Lorenzo L. Pesce, Rogan A. Grant, Mengjia Kang, Luisa Morales-Nebreda, Avni A. Bavishi, Jason M. Arnold, Anna Pawlowski, Chao Qi, G. R. Scott Budinger, Benjamin D. Singer, Richard G. Wunderink
Summary: In patients with severe SARS-CoV-2 pneumonia requiring mechanical ventilation, bacterial superinfection occurs in 25% of patients at the time of intubation. Empirical antibiotic management based on guidelines leads to antibiotic overuse, while BAL-based management reduces antibiotic use significantly. VAP develops in 44% of patients and accurate identification relies on microbiologic analysis of BAL fluid.
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
(2021)
Article
Cell Biology
Sachin Surve, Simon C. Watkins, Alexander Sorkin
Summary: The study demonstrated that endogenous KRAS and NRAS are predominantly localized to the plasma membrane and do not colocalize with endosomal EGFR upon EGF stimulation. It was suggested that a small pool of surface EGFRs sustain signaling within the RAS-ERK1/2 pathway.
JOURNAL OF CELL BIOLOGY
(2021)
Article
Cell Biology
Mireia Perez Verdaguer, Tian Zhang, Joao A. Paulo, Steven Gygi, Simon C. Watkins, Hiroaki Sakurai, Alexander Sorkin
Summary: This study dissects the mechanisms of p38-induced endocytosis of EGFR using a pH-sensitive model, proposing a unifying model of crosstalk between multiple endocytosis pathways. The research reveals that p38-dependent EGFR endocytosis is essential for the interaction with the sigma 2 subunit of clathrin adaptor AP2, and is additive to CME induced by cytokines but constrained to internalizing ligand-free EGFRs due to Grb2 recruitment by ligand-activated EGFRs.
JOURNAL OF CELL BIOLOGY
(2021)
Article
Cell Biology
Jonathan Barroso-Gonzalez, Laura Garcia-Exposito, Pablo Galaviz, Michelle Lee Lynskey, Joshua A. M. Allen, SongMy Hoang, Simon C. Watkins, Hilda A. Pickett, Roderick J. O'Sullivan
Summary: Alternative lengthening of telomeres (ALT) is a telomere-elongation mechanism observed in 15% of cancer subtypes. Disruption of the MutSa DNA mismatch repair complex leads to striking telomere hyperextension in ALT cells. MutSa is specifically recruited to telomeres in ALT cells by associating with the PCNA subunit of the replisome, counteracting the role of BLM helicase in stabilizing hyper-extended telomeres and maintaining the survival of MutSa-deficient ALT cancer cells.
Article
Immunology
Clifford Guy, Diana M. Mitrea, Po-Chien Chou, Jamshid Temirov, Kate M. Vignali, Xueyan Liu, Hui Zhang, Richard Kriwacki, Marcel P. Bruchez, Simon C. Watkins, Creg J. Workman, Dario A. A. Vignali
Summary: This study reveals that the inhibitory receptor LAG3 interferes with TCR signaling and T cell activation by lowering the pH at the immune synapse, providing insights into the mechanism of action of LAG3 in inhibiting T cell function.
Article
Microbiology
Jacqueline D. Corry, Gwenddolen Kettenburg, Amit A. Upadhyay, Megan Wallace, Michelle M. Marti, Elizabeth R. Wonderlich, Stephanie J. Bissel, Kyndal Goss, Timothy J. Sturgeon, Simon C. Watkins, Douglas S. Reed, Steven E. Bosinger, Simon M. Barratt-Boyes
Summary: This study used a novel model of lethal avian influenza in nonhuman primates to investigate the mechanism of severe pneumonia caused by the virus. The researchers found that a potent innate immune response, including high-level production of interferons and inflammatory factors, drives severe disease by recruiting inflammatory cells and leading to the release of neutrophil extracellular traps. They also observed a specific form of cell death known as pyroptosis during lethal influenza. These findings shed light on the mechanisms driving severe influenza and could be targeted for therapeutic interventions to prevent acute lung injury in patients with severe influenza.
Article
Oncology
Huda I. Atiya, Leonard Frisbie, Ester Goldfeld, Taylor Orellana, Nicole Donnellan, Francesmary Modugno, Michael Calderon, Simon Watkins, Rugang Zhang, Esther Elishaev, Thing Rinda Soong, Anda Vlad, Lan Coffman
Summary: This study reveals that a subset of endometriosis-derived mesenchymal stem cells (enMSCs), characterized by loss of CD10 expression, support the growth of ovarian clear cell carcinoma (OCCC) through iron donation. This iron donation is essential for cancer growth and also confers sensitivity to ferroptosis-inducing therapy.
Article
Hematology
Lillian Tran, Bowen Xie, Edwyn Assaf, Ricardo Ferrari, Iraklis I. Pipinos, George P. Casale, Roberto Ivan Mota Alvidrez, Simon Watkins, Ulka Sachdev
Summary: This study found that genes related to ferroptosis are differentially expressed in skeletal muscle affected by PAD. Targeting ferroptosis may be a new therapeutic strategy to reduce PAD myopathy.
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
(2023)
Article
Medicine, Research & Experimental
Catherine A. Gao, Nikolay S. Markov, Thomas Stoeger, Anna Pawlowski, Mengjia Kang, Prasanth Nannapaneni, Rogan A. Grant, Chiagozie Pickens, James M. Walter, Jacqueline M. Kruser, Luke Rasmussen, Daniel Schneider, Justin Starren, Helen K. Donnelly, Alvaro Donayre, Yuan Luo, G. R. Scott Budinger, Richard G. Wunderink, Alexander V. Misharin, Benjamin D. Singer
Summary: This study aimed to determine the contribution of unsuccessful treatment of ventilator-associated pneumonia (VAP) to mortality for patients with severe pneumonia. By observing 585 mechanically ventilated patients with severe pneumonia and respiratory failure, it was found that the unsuccessful treatment of VAP was associated with higher mortality.
JOURNAL OF CLINICAL INVESTIGATION
(2023)
Article
Cell Biology
Thomas Stoeger, Rogan A. Grant, Alexandra C. McQuattie-Pimentel, Kishore R. Anekalla, Sophia S. Liu, Heliodoro Tejedor-Navarro, Benjamin D. Singer, Hiam Abdala-Valencia, Michael Schwake, Marie-Pier Tetreault, Harris Perlman, William E. Balch, Navdeep S. Chandel, Karen M. Ridge, Jacob Sznajder, Richard Morimoto, Alexander Misharin, G. R. Scott Budinger, Luis A. Nunes Amaral
Summary: The length of transcripts explains the majority of transcriptional changes observed during aging in mice and humans. The relative abundance of long transcripts is lower in aging, and antiaging interventions can counter this length association. Genes with the longest transcripts are associated with lifespan extension, while genes with the shortest transcripts are associated with lifespan shortening.