Article
Biochemistry & Molecular Biology
Tom E. Forshaw, Julie A. Reisz, Kimberly J. Nelson, Rajesh Gumpena, J. Reed Lawson, Thomas J. Jonsson, Hanzhi Wu, Jill E. Clodfelter, Lynnette C. Johnson, Cristina M. Furdui, W. Todd Lowther
Summary: Human peroxiredoxins (Prx) are involved in various cellular functions and diseases, and can be repaired by human sulfiredoxin (Srx), hydrogen sulfide (H2S), and glutathione (GSH) after being hyperoxidized. Studying engineered Prx2 and Prx3 dimers, it was found that loss of the active site interface can make variants more resistant to repair, and it was revealed for the first time potential cooperation between Prx isoforms and GSH and H2S in supporting Srx activity.
Article
Neurosciences
Yu Hong, Cecilie Katrin Kristiansen, Anbin Chen, Gonzalo Sanchez Nido, Lena Elise Hoyland, Mathias Ziegler, Gareth John Sullivan, Laurence A. Bindoff, Kristina Xiao Liang
Summary: Diseases caused by POLG mutations are the most common form of mitochondrial diseases, but the molecular mechanisms behind the lower survival rate in patients with compound heterozygous mutations are unknown. This study used an iPSC model to investigate the differences between homozygous and compound heterozygous genotypes in different cell types. The results showed that compound heterozygous NSCs exhibited more severe functional defects and downregulation of mitochondrial and metabolic pathways compared to homozygous NSCs.
EXPERIMENTAL NEUROLOGY
(2023)
Article
Biochemistry & Molecular Biology
Yanning Hao, Hong Jiang, Pratik Thapa, Na Ding, Aziza Alshahrani, Junichi Fujii, Michel B. Toledano, Qiou Wei
Summary: Non-small cell lung cancer (NSCLC) is associated with smoking, which causes oxidative stress and promotes the occurrence of mutations and aberrant signaling pathways. Knockout of the Srx-Prx4 axis reduces the number and size of lung tumors in mice, inhibits cell proliferation, and decreases intra-tumoral macrophage infiltration.
Article
Biochemistry & Molecular Biology
Feline W. Lindhout, Sybren Portegies, Robbelien Kooistra, Lotte J. Herstel, Riccardo Stucchi, Jessica J. A. Hummel, Nicky Scheefhals, Eugene A. Katrukha, Maarten Altelaar, Harold D. MacGillavry, Corette J. Wierenga, Casper C. Hoogenraad
Summary: Centrosomes play a crucial role in controlling axon formation in human iPSC-derived neurons, as depletion of centrioles results in various axon developmental defects. Loss of centrioles affects axonal microtubule reorganization, which is essential for proper axon development and function. Live-cell imaging reveals the impaired microtubule dynamics in axons lacking centrioles during early development.
Article
Cell Biology
Evelyn Knappe, Franziska Rudolph, Christine Klein, Philip Seibler
Summary: This study investigated the role of microglia in Parkinson's disease (PD) by generating human cellular models. The researchers found that microglia were activated and released cytokines in PD, and showed a preference for activating the chemotaxis pathway. They also discovered protein level changes in PD risk factor GPNMB upon stress in microglia.
Article
Multidisciplinary Sciences
Aaron M. Earley, Lena F. Burbulla, Dimitri Krainc, Rajeshwar Awatramani
Summary: Using single cell RNA sequencing, the study unraveled graded molecular identities during human neurogenesis from pluripotent stem cells. Differentiation platforms were established to model neural induction from stem cells, and the differentiated cell types were characterized by 10x single cell RNA sequencing.
SCIENTIFIC REPORTS
(2021)
Article
Biochemistry & Molecular Biology
In-Sung Song, Yu Jeong Jeong, Yena Jung, Young-Ho Park, Sungbo Shim, Sung Joo Kim, Dae-Woon Eom, Seung-Mo Hong, Peter C. W. Lee, Sun-Uk Kim, Sung-Wuk Jang
Summary: The study found that the Sulfiredoxin-Peroxiredoxin redox system and mitochondrial oxidative phosphorylation play crucial roles in maintaining the stemness and survival of colon cancer stem cells. The Nrf2/FoxM1-induced Srx-Prx redox system is considered a potential therapeutic target for eliminating CSCs in colon cancer.
Review
Cell Biology
Leonie M. Heger, Rachel M. Wise, J. Tabitha Hees, Angelika B. Harbauer, Lena F. Burbulla
Summary: This review assesses mitochondrial phenotypes in iPSC-derived neurons from PD patients, focusing on the role of mitochondrial respiration, morphology, trafficking, mitophagy, and calcium handling in health and disease. It also summarizes the unique advantages and challenges of iPSC disease modeling for future mechanistic and therapeutic applications, highlighting the importance of studying mitochondrial dynamics in PD pathophysiology.
Article
Biochemistry & Molecular Biology
Tobias Vahsen, Ariane Brault, Thierry Mourer, Simon Labbe
Summary: The study reveals that the sulfiredoxin Srx1 interacts with the transporter Str3 to facilitate heme import and is essential for optimal growth in the presence of hemin. Srx1 also partially protects hemin from degradation caused by hydrogen peroxide.
MOLECULAR MICROBIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Julian Krauskopf, Kristel Eggermont, Rodrigo Furtado Madeiro Da Costa, Sacha Bohler, Duncan Hauser, Florian Caiment, Theo M. de Kok, Catherine Verfaillie, Jos C. Kleinjans
Summary: Parkinson's disease is a neurodegenerative disease with both genetic and sporadic cases, affecting a significant portion of the elderly population. Induced pluripotent stem cells can be used to derive dopaminergic neurons for in vitro disease modeling and studying the pathomolecular mechanisms of PD.
MOLECULAR PSYCHIATRY
(2022)
Article
Biochemistry & Molecular Biology
Elizabeth R. R. Sharlow, Danielle C. C. Llaneza, Bhanu P. P. Tewari, Garnett A. A. Mingledorff, Anna J. J. Mendelson, Harald Sontheimer, George S. S. Bloom, John S. S. Lazo
Summary: Differentiating and maturing neurons show different chemosensitivities, with a higher hit rate for differentiating neurons. Chemoinformatic analyses confirmed differences in potential drug targets expressed during neuronal development. These studies suggest that neuronal developmental stages may exhibit unique chemosensitivities and neuro-inhibitory effects of drugs may vary depending on the developmental stage.
Article
Cell Biology
Maria Jose Castellanos-Montiel, Mathilde Chaineau, Anna Kristyna Franco-Flores, Ghazal Haghi, Dulce Carrillo-Valenzuela, Wolfgang E. E. Reintsch, Carol X. -Q. Chen, Thomas M. M. Durcan
Summary: Researchers have developed a three-dimensional model and optimized a workflow for its morphological, gene expression, protein, and functional profiling.
Article
Biochemistry & Molecular Biology
Elena V. Grigor'eva, Alena E. Kopytova, Elena S. Yarkova, Sophia V. Pavlova, Diana A. Sorogina, Anastasia A. Malakhova, Tuyana B. Malankhanova, Galina V. Baydakova, Ekaterina Y. Zakharova, Sergey P. Medvedev, Sofia N. Pchelina, Suren M. Zakian
Summary: GBA variants significantly increase the risk of Parkinson's disease. The p.N370S substitution in the GBA gene affects the stability of the lysosomal enzyme GCase in cells. In this study, iPSC-derived DA neurons from GBA-PD patients and GBA carriers showed decreased GCase activity compared to healthy donors. GBA-PD neurons also exhibited alterations in the activity of other lysosomal enzymes.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Neurosciences
Kaitlin Flannagan, Julia A. Stopperan, Brittany M. Hauger, Benjamin R. Troutwine, Colton R. Lysaker, Taylor A. Strope, Vivien Csikos Drummond, Caleb A. Gilmore, Natalie A. Swerdlow, Julia M. Draper, Cynthia M. Gouvion, Jay L. Vivian, Mohammad Haeri, Russell H. Swerdlow, Heather M. Wilkins
Summary: In this study, iPSC derived models were used to investigate mitochondrial dysfunction in Alzheimer's disease (AD). The results showed that neurons and cerebral organoids derived from AD subjects exhibited reduced mitochondrial respiration and cytochrome oxidase activity, with more significant defects in the female cohort. These findings underscore the importance of considering sex as a biological variable in cell culture studies.
FRONTIERS IN MOLECULAR NEUROSCIENCE
(2023)
Article
Cell Biology
Domiziana Costamagna, Valerie Casters, Marc Beltra, Maurilio Sampaolesi, Anja Van Campenhout, Els Ortibus, Kaat Desloovere, Robin Duelen
Summary: This study generated in vitro human neuromuscular junctions (NMJs) using a microfluidic strategy from patient-specific induced pluripotent stem cell (hiPSC) lines to model disease-relevant neuropathologic processes in hereditary spastic paraplegia (HSP). The unique strength of this NMJ model is its ability to generate lower motor neurons (MNs) and myotubes from autologous hiPSC origin while maintaining the genetic background of HSP patient donors. The study found that HSP-derived lines exhibited axonal swellings, reduced levels of SPASTIN protein, and impaired NMJ profiles, offering unique tools to study the pathologic mechanisms of HSP.
Article
Biochemistry & Molecular Biology
Swagata Ghatak, Nima Dolatabadi, Richard Gao, Yin Wu, Henry Scott, Dorit Trudler, Abdullah Sultan, Rajesh Ambasudhan, Tomohiro Nakamura, Eliezer Masliah, Maria Talantova, Bradley Voytek, Stuart A. Lipton
Summary: Early stages of human Alzheimer's disease (AD) show hyperexcitability in the brain, leading to extensive synapse loss and cognitive dysfunction, with no current disease-modifying therapy available. Utilizing human iPSC models may be a valuable tool for screening drugs to treat hyperexcitability and synaptic damage in AD, potentially increasing the chances of success in treatment.
MOLECULAR PSYCHIATRY
(2021)
Review
Pharmacology & Pharmacy
Swagata Ghatak, Maria Talantova, Scott R. McKercher, Stuart A. Lipton
Summary: The balance between excitation and inhibition in a neuronal network, known as excitatory/inhibitory (E/I) balance, is crucial for normal brain function. In pathological conditions, this balance can be disrupted, leading to E/I imbalance and network dysfunction. Developing therapies to rebalance neural networks is important for improving neurological function in diseases associated with E/I imbalance.
ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 61, 2021
(2021)
Article
Neurosciences
Dorit Trudler, Sara Sanz-Blasco, Yvonne S. Eisele, Swagata Ghatak, Karthik Bodhinathan, Mohd Waseem Akhtar, William P. Lynch, Juan C. Pina-Crespo, Maria Talantova, Jeffery W. Kelly, Stuart A. Lipton
Summary: In Parkinson's disease, synaptic and neuronal loss are prominent features. The study reveals that alpha Syn oligomers induce excessive glutamate release from astrocytes, activating NMDARs on neurons and leading to synaptic damage. However, the drug NitroSynapsin shows promise in protecting synapses from alpha Syn-induced damage.
JOURNAL OF NEUROSCIENCE
(2021)
Article
Multidisciplinary Sciences
Tomohiro Nakamura, Chang-ki Oh, Lujian Liao, Xu Zhang, Kevin M. Lopez, Daniel Gibbs, Amanda K. Deal, Henry R. Scott, Brian Spencer, Eliezer Masliah, Robert A. Rissman, John R. Yates, Stuart A. Lipton
Summary: This study describes mechanistically distinct enzymes that can mediate a series of redox reactions and lead to synapse loss in patients with Alzheimer's disease. These enzymes can form a separate network for aberrant transnitrosylation, which may not be effectively countered by natural selection in the post-reproductive period.
Article
Multidisciplinary Sciences
Elaine Pirie, Chang-Ki Oh, Xu Zhang, Xuemei Han, Piotr Cieplak, Henry R. Scott, Amanda K. Deal, Swagata Ghatak, Fernando J. Martinez, Gene W. Yeo, John R. Yates, Tomohiro Nakamura, Stuart A. Lipton
Summary: This study reveals that environmentally induced nitrosative stress can trigger protein aggregation and cell-to-cell spread, leading to abnormal aggregation of TDP-43 in ALS/FTD. These processes also interfere with neuronal function, contributing to the progression of the diseases.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Biochemistry & Molecular Biology
Tomohiro Nakamura, Chang-ki Oh, Xu Zhang, Steven R. Tannenbaum, Stuart A. Lipton
Summary: Physiological concentrations of nitric oxide and related reactive nitrogen species play important roles in mediating signaling pathways in the nervous system. S-nitrosylation, particularly through transnitrosylation, is a critical chemical mechanism for transduction of redox-mediated events. Future studies should focus on understanding how transnitrosylation regulates various neuronal attributes in aging, inflammation, and neurodegenerative diseases.
ANTIOXIDANTS & REDOX SIGNALING
(2021)
Article
Neurosciences
Stuart A. Lipton, Paschalis-Thomas Doulias, Tomohiro Nakamura, Henry Scott, Abdullah Sultan, Scott R. McKercher, Amanda Deal, Matthew Albertolle, Harry Ischiropoulos
Summary: Both HIV-1 and methamphetamine use lead to increased oxidative and nitrosative stress in the brain, potentially contributing to cognitive impairment and worsening effects of drug abuse. Enhanced S-nitrosylation of proteins derived from nitric oxide may disrupt protein activity, particularly impacting TCA enzymes and leading to energy collapse observed in HAND and methamphetamine use.
JOURNAL OF NEUROVIROLOGY
(2021)
Article
Multidisciplinary Sciences
Dorit Trudler, Kristopher L. Nazor, Yvonne S. Eisele, Titas Grabauskas, Nima Dolatabadi, James Parker, Abdullah Sultan, Zhenyu Zhong, Marshall S. Goodwin, Yona Levites, Todd E. Golde, Jeffery W. Kelly, Michael R. Sierks, Nicholas J. Schork, Michael Karin, Rajesh Ambasudhan, Stuart A. Lipton
Summary: Parkinson's disease is associated with the accumulation of alpha-synuclein and activation of microglia, potentially leading to neuronal death. This study shows that alpha-synuclein can activate NLRP3 inflammasome in human microglia and that alpha-synuclein-antibody complexes can exacerbate inflammation in a human context.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Review
Biochemistry & Molecular Biology
Tomohiro Nakamura, Chang-ki Oh, Xu Zhang, Stuart A. Lipton
Summary: Neurodegenerative disorders such as Alzheimer's and Parkinson's diseases are characterized by progressive degeneration of synapses and neurons, often attributed to accumulated misfolded/aggregated proteins. Excessive reactive oxygen and nitrogen species in the brain may contribute to protein misfolding, potentially exacerbated by genetic mutations and environmental factors. Understanding the role of reactive nitrogen species in post-translational modifications of proteins could lead to therapeutic interventions for neurodegenerative diseases.
FREE RADICAL BIOLOGY AND MEDICINE
(2021)
Article
Immunology
Hongxu Xian, Yuan Liu, Alexandra Rundberg Nilsson, Raphaella Gatchalian, Timothy R. Crother, Warren G. Tourtellotte, Yi Zhang, German R. Aleman-Muench, Gavin Lewis, Weixuan Chen, Sarah Kang, Melissa Luevanos, Dorit Trudler, Stuart A. Lipton, Pejman Soroosh, John Teijaro, Juan Carlos de la Torre, Moshe Arditi, Michael Karin, Elsa Sanchez-Lopez
Summary: The study found that metformin can attenuate COVID-19-induced ARDS by inhibiting NLRP3 inflammasome activation, IL-1 beta and IL-6 secretion, and by blocking ATP and mtDNA synthesis.
Review
Biochemistry & Molecular Biology
Dorit Trudler, Swagata Ghatak, Stuart A. Lipton
Summary: Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, represent a significant social and economic burden due to increasing prevalence and lack of effective therapies. Lack of reliable models has hindered the development of treatments, but human-induced pluripotent stem cell technology offers a promising alternative to complement animal models for disease modeling and drug discovery.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Neurosciences
Chang-Ki Oh, Nima Dolatabadi, Piotr Cieplak, Maria T. Diaz-Meco, Jorge Moscat, John P. Nolan, Tomohiro Nakamura, Stuart A. Lipton
Summary: This article investigates the mechanism by which dysregulation of autophagic pathways leads to the accumulation of abnormal proteins and damaged organdies in neurodegenerative disorders. The authors found that pathologic protein S-nitrosylation of p62 is a critical factor for autophagic inhibition and cell-to-cell spread.
JOURNAL OF NEUROSCIENCE
(2022)
Review
Biochemistry & Molecular Biology
Takumi Satoh, Dorit Trudler, Chang-Ki Oh, Stuart A. Lipton
Summary: This article reviews the potential applications of carnosic acid (CA) and carnosol (CS) in rosemary for conditions such as Alzheimer's disease, Parkinson's disease, and COVID-19. It highlights the antioxidant, anti-inflammatory, and neuroprotective effects of CA, as well as its potential to inhibit the NLRP3 inflammasome. The article suggests that CA-related compounds could serve as therapeutics for acute and chronic neurological effects caused by SARS-CoV-2 infection and other neurodegenerative diseases.
Article
Biochemistry & Molecular Biology
Ki-Ryeong Kim, Eun-Jung Cho, Jae-Won Eom, Sang-Seok Oh, Tomohiro Nakamura, Chang-ki Oh, Stuart A. Lipton, Yang-Hee Kim
Summary: This study reveals that S-nitrosylation of lysosomal protease cathepsin B (CTSB) inhibits its activity, blocks autophagic flux, and contributes to the pathogenesis of Alzheimer's disease (AD).
CELL DEATH AND DIFFERENTIATION
(2022)
