Review
Biochemistry & Molecular Biology
Keith Mayl, Christopher E. Shaw, Youn-Bok Lee
Summary: A hexanucleotide repeat expansion mutation in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia, likely driven by toxic gain of function from bidirectionally transcribed repeat RNA. Multiple pathogenic mechanisms have been proposed and some novel therapeutic approaches are currently in development.
Review
Neurosciences
Daniel A. Solomon, Rebekah Smikle, Matthew J. Reid, Sarah Mizielinska
Summary: The article discusses the cellular phase separation mechanism in C9orf72-ALS/FTD, highlighting the impact of toxic proteins and RNA on membraneless organelles, and the potential pathological cellular phenomena that may result.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2021)
Article
Multidisciplinary Sciences
Wei Shao, Tiffany W. Todd, Yanwei Wu, Caroline Y. Jones, Jimei Tong, Karen Jansen-West, Lillian M. Daughrity, Jinyoung Park, Yuka Koike, Aishe Kurti, Mei Yue, Monica Castanedes-Casey, Giulia del Rosso, Judith A. Dunmore, Desiree Zanetti Alepuz, Bjorn Oskarsson, Dennis W. Dickson, Casey N. Cook, Mercedes Prudencio, Tania F. Gendron, John D. Fryer, Yong-Jie Zhang, Leonard Petrucelli
Summary: Frontotemporal dementia and amyotrophic lateral sclerosis (FTD-ALS) are linked to mutations in the C9orf72 and TBK1 genes. This study demonstrates that TBK1 is phosphorylated and sequestered by C9orf72 poly(GA) aggregates, leading to a loss of TBK1 activity and contributing to neurodegeneration. Inhibition of the endosomal pathway exacerbates poly(GA)-induced phenotypes, highlighting the importance of this pathway and TBK1 activity in FTD-ALS pathogenesis.
Article
Chemistry, Medicinal
Aifang Cheng, Changdong Liu, Wenkang Ye, Duli Huang, Weiyi She, Xin Liu, Chun Po Fung, Naining Xu, Monica Ching Suen, Wei Ye, Herman Ho Yung Sung, Ian Duncan Williams, Guang Zhu, Pei -Yuan Qian
Summary: This study identified three first-in-class marine natural products, cA, cB, and cC, which selectively bind to G4C2 G4s and show remarkable bioactivities. Particularly, cA and cC can reduce cell death caused by G4C2 EHR and improve pathological features of related diseases.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
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
Multidisciplinary Sciences
Gopinath Krishnan, Denitza Raitcheva, Daniel Bartlett, Mercedes Prudencio, Diane M. McKenna-Yasek, Catherine Douthwright, Bjorn E. Oskarsson, Shafeeq Ladha, Oliver D. King, Sami J. Barmada, Timothy M. Miller, Robert Bowser, Jonathan K. Watts, Leonard Petrucelli, Robert H. Brown, Mark W. Kankel, Fen-Biao Gao
Summary: The GGGGCC repeat expansion in C9ORF72 is a common genetic cause of ALS and FTD, leading to the production of five DPR proteins. Sensitive assays have been developed to detect poly(GA) and poly(GR) levels in the CSF of C9ORF72 mutation carriers. The levels of these DPR proteins do not correlate with disease characteristics but decrease with ASO treatment, suggesting their potential as fluid-based biomarkers.
NATURE COMMUNICATIONS
(2022)
Article
Cell Biology
Steven Rodriguez, Asli Sahin, Benjamin R. Schrank, Hawra Al-Lawati, Isabel Costantino, Eric Benz, Darian Fard, Alefiya D. Albers, Luxiang Cao, Alexis C. Gomez, Kyle Evans, Elena Ratti, Merit Cudkowicz, Matthew P. Frosch, Michael Talkowski, Peter K. Sorger, Bradley T. Hyman, Mark W. Albers
Summary: The study discovered the presence of cdsRNA in the brains of ALS-FTD patients, coinciding with TDP-43 inclusions and inducing IFN-I signaling and cell death. Mouse experiments showed that genomically encoded dsRNA triggered IFN-I and death in connected neurons, potentially driving neuroinflammation and neurodegeneration in ALS/FTD patients.
SCIENCE TRANSLATIONAL MEDICINE
(2021)
Article
Neurosciences
Anna L. Gill, Alan S. Premasiri, Fernando G. Vieira
Summary: Hexanucleotide repeat expansion mutations in the C9ORF72 gene contribute to a significant portion of familial ALS and FTD cases, as well as a percentage of sporadic ALS cases. These mutations lead to the production of dipeptide repeat proteins, including cytotoxic polyGR and polyPR. Methylation of arginine residues in polyGR/polyPR may play a role in neurodegeneration processes associated with G4C2(n) mutations.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2021)
Review
Neurosciences
Layla T. Ghaffari, Davide Trotti, Aaron R. Haeusler, Brigid K. Jensen
Summary: ALS is a progressive neurodegenerative disease with heterogeneous clinical manifestations and lack of effective treatment. Cortical hyper-excitability is observed early in the disease and is associated with nucleotide repeat expansion in the C9ORF72 gene. ALS and FTD are part of a disease spectrum, both characterized by synaptic dysfunction.
FRONTIERS IN MOLECULAR NEUROSCIENCE
(2022)
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)
Article
Biology
Janani Parameswaran, Nancy Zhang, Elke Braems, Kedamawit Tilahun, Devesh C. Pant, Keena Yin, Seneshaw Asress, Kara Heeren, Anwesha Banerjee, Emma Davis, Samantha L. Schwartz, Graeme L. Conn, Gary J. Bassell, Ludo van den Bosch, Jie Jiang
Summary: GGGGCC (G(4)C(2)) repeat expansion in C9ORF72 gene is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Our study shows that C9ORF72 antisense C(4)G(2) repeat expanded RNAs activate the PKR/eIF2a-dependent integrated stress response, leading to translation inhibition and stress granule formation. PKR levels reduction mitigates stress response and toxicity caused by the antisense C(4)G(2) RNAs. Increased phosphorylation of PKR/eIF2a is also observed in the frontal cortex of C9ORF72 FTD/ALS patients. Only antisense C(4)G(2) repeat expanded RNAs activate the PKR/eIF2a pathway and induce aberrant stress granule formation.
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)
Review
Biochemistry & Molecular Biology
Weilun Pang, Fenghua Hu
Summary: The hexanucleotide repeat expansion in the C9ORF72 gene is a major cause of ALS and FTD. C9ORF72, along with SMCR8 and WDR41, forms a tight complex involved in various cellular processes, including regulation of inflammation mediators trafficking and degradation.
JOURNAL OF NEUROCHEMISTRY
(2021)
Article
Biology
Yoshifumi Sonobe, Soojin Lee, Gopinath Krishnan, Yuanzheng Gu, Deborah Y. Kwon, Fen-Biao Gao, Raymond P. Roos, Paschalis Kratsios
Summary: A hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of ALS and FTD. Translation of DPR proteins depends on non-canonical initiation codons, but the study found that two antisense DPRs, poly-PR and poly-PG, are translated using canonical AUG codons.
Article
Clinical Neurology
Claudia S. Bauer, Rebecca N. Cohen, Francesca Sironi, Matthew R. Livesey, Thomas H. Gillingwater, J. Robin Highley, Daniel J. Fillingham, Ian Coldicott, Emma F. Smith, Yolanda B. Gibson, Christopher P. Webster, Andrew J. Grierson, Caterina Bendotti, Kurt J. De Vos
Summary: A GGGGCC hexanucleotide repeat expansion in the C9ORF72 gene is the main genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. This study shows that C9orf72 protein interacts with the synapsin family of synaptic vesicle proteins, and C9orf72 deficiency reduces the number of excitatory synapses and synapsin levels, leading to synaptic dysfunction.
ACTA NEUROPATHOLOGICA
(2022)
Article
Clinical Neurology
Stephen Moore, Eric Alsop, Ileana Lorenzini, Alexander Starr, Benjamin E. Rabichow, Emily Mendez, Jennifer L. Levy, Camelia Burciu, Rebecca Reiman, Jeannie Chew, Veronique V. Belzil, Dennis W. Dickson, Janice Robertson, Kim A. Staats, Justin K. Ichida, Leonard Petrucelli, Kendall Van Keuren-Jensen, Rita Sattler
ACTA NEUROPATHOLOGICA
(2019)
Article
Neurosciences
Laura Stertz, Jessica Di Re, Guangsheng Pei, Gabriel R. Fries, Emily Mendez, Shenglan Li, Laura Smith-Callahan, Henriette Raventos, Jerricho Tipo, Rohan Cherukuru, Zhongming Zhao, Ying Liu, Peilin Jia, Fernanda Laezza, Consuelo Walss-Bass
Summary: This study utilized human-induced pluripotent stem cells (hiPSCs) derived from schizophrenia (SCZ) patients in the isolated population of the Central Valley of Costa Rica for RNA-sequencing analysis, identifying differentially expressed genes enriched in the phosphoinositide 3-kinase/glycogen synthase kinase 3 (PI3K/GSK3) signaling pathway, and suggesting disruption of the PI3K/GSK3 signaling pathway as a potential risk factor for SCZ.
NEUROPSYCHOPHARMACOLOGY
(2021)
Article
Clinical Neurology
Andi Liu, Yulin Dai, Emily F. Mendez, Ruifeng Hu, Gabriel R. Fries, Katherine E. Najera, Shan Jiang, Thomas D. Meyer, Laura Stertz, Peilin Jia, Consuelo Walss-Bass, Zhongming Zhao
Summary: The study identified differences in gene and epigenetic changes in OUD patients related to astrocyte and glial cell differentiation, suggesting the involvement of complex gene regulatory mechanisms in OUD. Cross-omics analysis revealed OUD-specific immune-related transcription regulators, providing new insights into the disease pathogenesis.
INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Emily F. Mendez, Haichao Wei, Ruifeng Hu, Laura Stertz, Gabriel R. Fries, Xizi Wu, Katherine E. Najera, Michael D. Monterey, Christie M. Lincoln, Joo-won Kim, Karla Moriel, Thomas D. Meyer, Sudhakar Selvaraj, Antonio L. Teixeira, Zhongming Zhao, Junqian Xu, Jiaqian Wu, Consuelo Walss-Bass
Summary: Opioid use disorder (OUD) is a major public health crisis in the U.S., causing over 50 thousand deaths annually due to overdose. By integrating RNA and protein analysis, the study identified dysregulation of angiogenic gene networks in OUD subjects, with cell type-specific effects observed in astrocyte, endothelial, and microglia correlated genes. Understanding the neurovascular effects of OUD is crucial in the current era of widespread opioid use.
MOLECULAR PSYCHIATRY
(2021)
Article
Psychiatry
Sandra L. Grimm, Emily F. Mendez, Laura Stertz, Thomas D. Meyer, Gabriel R. Fries, Tanmay Gandhi, Rupa Kanchi, Sudhakar Selvaraj, Antonio L. Teixeira, Thomas R. Kosten, Preethi Gunaratne, Cristian Coarfa, Consuelo Walss-Bass
Summary: To understand the mechanisms and potential targets for intervention in opioid use disorder, researchers examined postmortem brains and blood samples to explore the role of microRNAs (miRNA) in gene regulation. They found that miRNAs identified in the brains and blood had distinct profiles but targeted the same genes and pathways related to tissue development, morphogenesis, and MAPK signaling pathways. Additionally, the study identified cell-type specific miRNA targets associated with opioid use disorder and revealed correlations with various biological processes and pathways. These findings shed new light on the impact of opioid drugs and provide potential leads for intervention.
FRONTIERS IN PSYCHIATRY
(2023)
Article
Psychiatry
Emily F. F. Mendez, Sandra L. L. Grimm, Laura Stertz, Damian Gorski, Sai V. V. Movva, Katherine Najera, Karla Moriel, Thomas D. D. Meyer, Gabriel R. R. Fries, Cristian Coarfa, Consuelo Walss-Bass
Summary: This study developed a model of neural progenitor cells and neurons derived from induced pluripotent stem cells (iPSCs) generated from postmortem human skin fibroblasts, and compared them to isogenic brain tissue. The results showed that this model effectively recapitulated drug-induced alterations in gene expression, providing new insights into substance use disorders.
FRONTIERS IN PSYCHIATRY
(2023)
Meeting Abstract
Neurosciences
Emily Mendez, Haichao Wei, Laura Stertz, Gabriel Fries, Ruifeng Hu, Xizi Wu, Katherine Najera, Karla Moriel, Thomas Meyer, Zhongming Zhao, Jiaqian Wu, Consuelo Walss-Bass
BIOLOGICAL PSYCHIATRY
(2021)
Article
Ophthalmology
Preeti Subramanian, Emily F. Mendez, S. Patricia Becerra
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
(2016)
Meeting Abstract
Biochemistry & Molecular Biology
Preeti Subramanian, Emily Mendez, S. Patricia Becerra
Article
Neurosciences
Xiaomei Lin, Tianyuyi Feng, Erheng Cui, Yunfei Li, Zhang Qin, Xiaohu Zhao
Summary: This study successfully established a rat model based on the genetic-environmental interaction, which exhibited phenotype characteristics similar to human AD in terms of cognitive function, brain microstructure, and immunohistochemistry. The genetic factor (APP mutation) and the environmental factor (acrolein exposure) accounted for 39.74% and 33.3% of the AD-like phenotypes in the model, respectively.
Article
Neurosciences
Gustavo Guimara Guerrero, Giovanna Bignoto Minhoto, Camilla dos Santos Tiburcio-Machado, Itza Amarisis Ribeiro Pinto, Claudio Antonio Federico, Marcia Carneiro Valera
Summary: The present study evaluated the influence of head and neck radiotherapy on the behavior and body weight gain in Wistar rats. The results demonstrated that different doses of radiation induced depressive behavior in the animals, and that the weight gain tended to be lower in the irradiated groups.
Article
Neurosciences
Ziwei Gao, Chao Lu, Yaping Zhu, Yuxin Liu, Yuesong Lin, Wenming Gao, Liyuan Tian, Lei Wu
Summary: This study reveals the underlying mechanisms of the rapid antidepressant effects of merazin hydrate (MH), which activates CaMKII to promote neuronal activities and proliferation in the hippocampus.
Article
Neurosciences
Kathleen E. Murray, Whitney A. Ratliff, Vedad Delic, Bruce A. Citron
Summary: Gulf War Illness (GWI) is a chronic disorder that affects approximately 30% of Veterans deployed to the Persian Gulf. This study found that exposure to toxicants during the Gulf War resulted in long-term changes in the morphology of dentate granule cells and that treatment with Nrf2 activator could improve neuronal health in the hippocampus.
Article
Neurosciences
Jing Li, Yan Zou, Xiangchuang Kong, Yangming Leng, Fan Yang, Guofeng Zhou, Bo Liu, Wenliang Fan
Summary: This study examines the functional connectivity changes in individuals with sudden sensorineural hearing loss (SSNHL) at the integrity, network, and edge levels. The findings reveal reduced intranetwork connectivity strength and increased internetwork connectivity in SSNHL patients. These alterations are associated with the duration of SSNHL and Tinnitus Handicap Inventory scores. The study provides crucial insights into the neural mechanisms of SSNHL and the brain's network-level responses to sensory loss.
Review
Neurosciences
Didier Majou, Anne-Lise Dermenghem
Summary: In the early stages of SAD, memory impairment is strongly correlated with cortical levels of soluble amyloid-beta peptide oligomers. A beta disrupts glutamatergic synaptic function and leads to cognitive deficits. This article describes the pathogenic mechanisms underlying cerebral amyloidosis, involving amyloid precursor protein synthesis, A beta residue clearance processes, and the role of specific molecules.
Article
Neurosciences
Jing Li, Yi Shan, Xiaojing Zhao, Guixiang Shan, Peng-Hu Wei, Lin Liu, Changming Wang, Hang Wu, Weiqun Song, Yi Tang, Guo-Guang Zhao, Jie Lu
Summary: This study investigates changes in brain anatomical structures and functional network connectivity after chronic complete thoracic spinal cord injury (cctSCI) and their impact on clinical outcomes. The findings reveal alterations in gray matter volume and functional connectivity in specific brain regions, indicating potential therapeutic targets and methods for tracking treatment outcomes.
Article
Neurosciences
Anllely Fernandez, Katherine Corvalan, Octavia Santis, Maxs Mendez-Ruette, Ariel Caviedes, Matias Pizarro, Maria -Teresa Gomez, Luis Federico Batiz, Peter Landgraf, Thilo Kahne, Alejandro Rojas-Fernandez, Ursula Wyneken
Summary: This study reveals the importance of SUMOylation in modulating the protein cargo of astrocyte-derived small extracellular vesicles (sEVs) and its potential impact on neurons.
Article
Neurosciences
Anika Luettig, Stefanie Perl, Maria Zetsche, Franziska Richter, Denise Franz, Marco Heerdegen, Ruediger Koehling, Angelika Richter
Summary: This study found that changes in c-Fos activity during short-term stimulation of the entopeduncular nucleus (EPN) are associated with improvement in dystonia, and also discovered that the cerebellum may be involved in the antidystonic effects.
Article
Neurosciences
Yanlin Tao, Wei Shen, Houyuan Zhou, Zikang Li, Ting Pi, Hui Wu, Hailian Shi, Fei Huang, Xiaojun Wu
Summary: Depression has a higher incidence in women compared to men, and this study investigated the impact of sex on depressive behaviors and underlying mechanisms using a corticosterone-induced depression model in mice. The results showed sex-specific anxiety and depression behaviors in the model group, as well as differences in protein expression and neurotransmitter levels between male and female mice. These findings enhance our understanding of sex-specific differences in depression and support tailored interventions.
Review
Neurosciences
Dnyandev G. Gadhave, Vrashabh V. Sugandhi, Chandrakant R. Kokare
Summary: This article discusses the characteristics and importance of the tight junctions of endothelial cells in the CNS, which act as a biological barrier known as the blood-brain barrier (BBB). It focuses on overcoming the challenges of delivering therapeutic agents to the brain in neurodegenerative disorders, particularly multiple sclerosis, through the use of biomaterials. The article also highlights the current limitations of animal models for studying multiple sclerosis and suggests a potential future research direction.
Article
Neurosciences
Li-Min Mao, Khyathi Thallapureddy, John Q. Wang
Summary: Propofol can enhance synapsin phosphorylation and modulate synaptic transmission in the mouse brain. The study reveals the potential role of synapsin as a substrate of propofol and its effects on neurotransmitter release machinery.
Article
Neurosciences
Syed Maaz Ahmed Rizvi, Abdul Baseer Buriro, Irfan Ahmed, Abdul Aziz Memon
Summary: This study explores the effects of prolonged mask usage on the human brain by analyzing EEG and physiological parameters. The results show that the mean EEG spectral power in alpha, beta, and gamma sub-bands of individuals wearing masks is smaller than those without masks. The performances on cognitive tasks and oxygen saturation level differ between the two groups, while blood pressure, body temperature, and heart rate are similar. The analysis also reveals that the occipital and frontal lobes exhibit the greatest variability in channel measurements.
Article
Neurosciences
Rui-Fang Ma, Lu-Lu Xue, Jin-Xiang Liu, Li Chen, Liu-Lin Xiong, Ting-Hua Wang, Fei Liu
Summary: This study observed changes in brain infarction and blood vessels in rats during neonatal hypoxic ischemic encephalopathy (NHIE) modeling using Transcranial Doppler Ultrasonography (TCD). Longer duration of hypoxia was associated with more severe nerve damage. TCD can dynamically monitor cerebral infarction after NHIE modeling, which may serve as a useful auxiliary method for evaluating animal experimental models.
Article
Neurosciences
Yuxiang Dai, Chen Yu, Lu Zhou, Longyang Cheng, Hongbin Ni, Weibang Liang
Summary: Overexpression of CXCR4 in glioma is correlated with patient survival, and its inhibition can reduce invasion and migration of glioma cells. Inhibiting Nur77 also decreases cancer progression associated with CXCR4.