scholarly journals Resveratrol and related stilbene-derivatives induce Stress Granules with distinct clearance kinetics

2021 ◽  
pp. mbc.E21-02-0066
Author(s):  
Triana Amen ◽  
Anthony Guihur ◽  
Christina Zelent ◽  
Robertas Ursache ◽  
Jörg Wilting ◽  
...  
Keyword(s):  
Survival Function ◽  
Chemotherapy Resistance ◽  
Stress Granules ◽  
Live Cells ◽  
Key Factor ◽  
Stilbene Derivatives ◽  
Rapid Clearance ◽  
Cellular Pathways ◽  
Clearance Kinetics ◽  
Lateral Sclerosis

Stress Granules are ribonucleoprotein functional condensates that form during stress conditions in all eukaryotic cells. Although their stress-survival function is far from clear, Stress Granules have been implicated in the regulation of many vital cellular pathways. Consequently, SG dysfunction is thought to be a mechanistic point of origin for many neurodegenerative disorders, including Amyotrophic Lateral Sclerosis (ALS). Additionally, SGs are thought to play a role in pathogenic pathways as diverse as viral infection and chemotherapy resistance. There is a growing consensus around the hypothesis that understanding the mechanistic regulation of SG physical properties is essential to understanding their function. Although the internal dynamics and condensation mechanisms of SGs have been broadly investigated, there have been fewer investigations into the timing of SG formation and clearance in live cells. Since the lifetime of SG persistence can be a key factor in their function and tendency towards pathological dysregulation, SG clearance mechanisms deserve particular attention. Here we show that resveratrol and its analogues, piceatannol, pterostilbene, and 3,4,5,4′ tetramethoxystilbene induce G3BP-dependent SG formation with atypically rapid clearance kinetics. Resveratrol binds to G3BP, thereby reducing its protein-protein association valency. We suggest that altering G3BP valency is a pathway for the formation of uniquely transient SGs.

scholarly journals Dysregulation of lipid metabolism and pathological inflammation in patients with COVID-19

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Marianna Caterino ◽  
Monica Gelzo ◽  
Stefano Sol ◽  
Roberta Fedele ◽  
Anna Annunziata ◽  
...  
Keyword(s):  
Virus Entry ◽  
Critical Role ◽  
Membrane Vesicles ◽  
Virus Propagation ◽  
Lipidomic Analysis ◽  
Key Factor ◽  
Patient Profiles ◽  
Cellular Pathways ◽  
Severity Degree

AbstractIn recent months, Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread throughout the world. COVID-19 patients show mild, moderate or severe symptoms with the latter ones requiring access to specialized intensive care. SARS-CoV-2 infections, pathogenesis and progression have not been clearly elucidated yet, thus forcing the development of many complementary approaches to identify candidate cellular pathways involved in disease progression. Host lipids play a critical role in the virus life, being the double-membrane vesicles a key factor in coronavirus replication. Moreover, lipid biogenesis pathways affect receptor-mediated virus entry at the endosomal cell surface and modulate virus propagation. In this study, targeted lipidomic analysis coupled with proinflammatory cytokines and alarmins measurement were carried out in serum of COVID-19 patients characterized by different severity degree. Serum IL-26, a cytokine involved in IL-17 pathway, TSLP and adiponectin were measured and correlated to lipid COVID-19 patient profiles. These results could be important for the classification of the COVID-19 disease and the identification of therapeutic targets.

scholarly journals Small molecules for modulating protein driven liquid-liquid phase separation in treating neurodegenerative disease

2019 ◽  
Author(s):  
Richard J. Wheeler ◽  
Hyun O. Lee ◽  
Ina Poser ◽  
Arun Pal ◽  
Thom Doeleman ◽  
...  
Keyword(s):  
Phase Separation ◽  
Neurodegenerative Disease ◽  
Stress Granules ◽  
Life Time ◽  
Stress Granule ◽  
Phase Behaviour ◽  
Granule Proteins ◽  
Lateral Sclerosis ◽  
Liquid Liquid Phase Separation

AbstractAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with few avenues for treatment. Many proteins implicated in ALS associate with stress granules, which are examples of liquid-like compartments formed by phase separation. Aberrant phase transition of stress granules has been implicated in disease, suggesting that modulation of phase transitions could be a possible therapeutic route. Here, we combine cell-based and protein-based screens to show that lipoamide, and its related compound lipoic acid, reduce the propensity of stress granule proteins to aggregate in vitro. More significantly, they also prevented aggregation of proteins over the life time of Caenorhabditis elegans. Observations that they prevent dieback of ALS patient-derived (FUS mutant) motor neuron axons in culture and recover motor defects in Drosophila melanogaster expressing FUS mutants suggest plausibility as effective therapeutics. Our results suggest that altering phase behaviour of stress granule proteins in the cytoplasm could be a novel route to treat ALS.

scholarly journals Antisense Transcription across Nucleotide Repeat Expansions in Neurodegenerative and Neuromuscular Diseases: Progress and Mysteries

Genes ◽  
2020 ◽  
Vol 11 (12) ◽  
pp. 1418
Author(s):  
Ana F. Castro ◽  
Joana R. Loureiro ◽  
José Bessa ◽  
Isabel Silveira
Keyword(s):  
Gene Expression ◽  
Neuromuscular Diseases ◽  
Antisense Transcription ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 7 ◽  
Repeat Expansions ◽  
Cellular Pathways ◽  
The Impact ◽  
Lateral Sclerosis

Unstable repeat expansions and insertions cause more than 30 neurodegenerative and neuromuscular diseases. Remarkably, bidirectional transcription of repeat expansions has been identified in at least 14 of these diseases. More remarkably, a growing number of studies has been showing that both sense and antisense repeat RNAs are able to dysregulate important cellular pathways, contributing together to the observed clinical phenotype. Notably, antisense repeat RNAs from spinocerebellar ataxia type 7, myotonic dystrophy type 1, Huntington’s disease and frontotemporal dementia/amyotrophic lateral sclerosis associated genes have been implicated in transcriptional regulation of sense gene expression, acting either at a transcriptional or posttranscriptional level. The recent evidence that antisense repeat RNAs could modulate gene expression broadens our understanding of the pathogenic pathways and adds more complexity to the development of therapeutic strategies for these disorders. In this review, we cover the amazing progress made in the understanding of the pathogenic mechanisms associated with repeat expansion neurodegenerative and neuromuscular diseases with a focus on the impact of antisense repeat transcription in the development of efficient therapies.

scholarly journals The role of mutated SOD1 gene in synaptic stripping and MHC class I expression following nerve axotomy in ALS murine model

2018 ◽  
Author(s):  
Roman M. Kassa ◽  
Roberta Bonafede ◽  
Federico Boschi ◽  
Manuela Malatesta ◽  
Raffaella Mariotti
Keyword(s):  
Mhc Class I ◽  
Murine Model ◽  
Excitatory Input ◽  
Class I ◽  
Facial Motoneurons ◽  
Cellular Pathways ◽  
First Time ◽  
Lateral Sclerosis ◽  
Mhc Class I Molecules

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motoneuron death. Several cellular pathways have been described to be involved in ALS pathogenesis; however, the involvement of presynaptic stripping and the related MHC class I molecules in mutant SOD1 motoneurons remains to be clarified. To this purpose, we here investigated, for the first time, the motoneurons behavior, di per seand after facial axonal injury, in terms of synaptic stripping and MHC class I expression in wild-type (Wt) mice and in a murine model of ALS, the SOD1(G93A) mice, at the presymptomatic and symptomatic stage of the disease. Concerning Wt animals, we found a reduction in synaptophysin immunoreactivity and an increase of MHC class I molecules in facial motoneurons after axotomy. In uninjured motoneurons of SOD1(G93A) mice, an altered presynaptic framework was evident, and this phenomenon increased during the disease course. The alteration in the presynaptic input is related to excitatory fibers. Moreover, after injury, a further decrease of excitatory input was not associated to an upregulation of MHC class I molecules in motoneuron soma. This study demonstrates, for the first time, that the presence of mutated SOD1 protein affects the MHC class I molecules expression, altering the presynaptic input in motoneurons. Nevertheless, a positive MHC class I immunolabeling was evident in glial cells around facial injured motoneurons, underlying an involvement of these cells in synaptic stripping. This study contributes to better understand the involvement of the mutated SOD1 protein in the vulnerability of motoneurons after damage.

scholarly journals The PI3K and MAPK/p38 pathways control stress granule assembly in a hierarchical manner

2019 ◽  
Vol 2 (2) ◽  
pp. e201800257 ◽  
Author(s):  
Alexander Martin Heberle ◽  
Patricia Razquin Navas ◽  
Miriam Langelaar-Makkinje ◽  
Katharina Kasack ◽  
Ahmed Sadik ◽  
...  
Keyword(s):  
Systems Approach ◽  
Survival Function ◽  
Mammalian Target Of Rapamycin ◽  
Stress Granules ◽  
Stress Granule ◽  
Cancer Tissue ◽  
Human Breast Cancer Tissue ◽  
Granule Formation ◽  
The Impact ◽  
Hierarchical Manner

All cells and organisms exhibit stress-coping mechanisms to ensure survival. Cytoplasmic protein-RNA assemblies termed stress granules are increasingly recognized to promote cellular survival under stress. Thus, they might represent tumor vulnerabilities that are currently poorly explored. The translation-inhibitory eIF2α kinases are established as main drivers of stress granule assembly. Using a systems approach, we identify the translation enhancers PI3K and MAPK/p38 as pro-stress-granule-kinases. They act through the metabolic master regulator mammalian target of rapamycin complex 1 (mTORC1) to promote stress granule assembly. When highly active, PI3K is the main driver of stress granules; however, the impact of p38 becomes apparent as PI3K activity declines. PI3K and p38 thus act in a hierarchical manner to drive mTORC1 activity and stress granule assembly. Of note, this signaling hierarchy is also present in human breast cancer tissue. Importantly, only the recognition of the PI3K-p38 hierarchy under stress enabled the discovery of p38’s role in stress granule formation. In summary, we assign a new pro-survival function to the key oncogenic kinases PI3K and p38, as they hierarchically promote stress granule formation.

scholarly journals Ubiquitination of G3BP1 mediates stress granule disassembly in a context-specific manner

Science ◽  
2021 ◽  
Vol 372 (6549) ◽  
pp. eabf6548
Author(s):  
Youngdae Gwon ◽  
Brian A. Maxwell ◽  
Regina-Maria Kolaitis ◽  
Peipei Zhang ◽  
Hong Joo Kim ◽  
...  
Keyword(s):  
Specific Interaction ◽  
Interaction Network ◽  
Stress Granules ◽  
Stress Granule ◽  
Eukaryotic Cells ◽  
Central Protein ◽  
Specific Manner ◽  
Cultured Human Cells ◽  
Context Specific ◽  
Lateral Sclerosis

Stress granules are dynamic, reversible condensates composed of RNA and protein that assemble in eukaryotic cells in response to a variety of stressors and are normally disassembled after stress is removed. The composition and assembly of stress granules is well understood, but little is known about the mechanisms that govern disassembly. Impaired disassembly has been implicated in some diseases including amyotrophic lateral sclerosis, frontotemporal dementia, and multisystem proteinopathy. Using cultured human cells, we found that stress granule disassembly was context-dependent: Specifically in the setting of heat shock, disassembly required ubiquitination of G3BP1, the central protein within the stress granule RNA-protein network. We found that ubiquitinated G3BP1 interacted with the endoplasmic reticulum–associated protein FAF2, which engaged the ubiquitin-dependent segregase p97/VCP (valosin-containing protein). Thus, targeting of G3BP1 weakened the stress granule–specific interaction network, resulting in granule disassembly.

scholarly journals Partial Failure of Proteostasis Systems Counteracting TDP-43 Aggregates in Neurodegenerative Diseases

2019 ◽  
Vol 20 (15) ◽  
pp. 3685 ◽  
Author(s):  
Roberta Cascella ◽  
Giulia Fani ◽  
Alessandra Bigi ◽  
Fabrizio Chiti ◽  
Cristina Cecchi
Keyword(s):  
Neurodegenerative Disorders ◽  
Frontotemporal Lobar Degeneration ◽  
Strong Influence ◽  
Genetic Mutations ◽  
Oxygen Species ◽  
Caspase Activation ◽  
Post Translational Modifications ◽  
Key Factor ◽  
The Central Nervous System ◽  
Lateral Sclerosis

Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are progressive and fatal neurodegenerative disorders showing mislocalization and cytosolic accumulation of TDP-43 inclusions in the central nervous system. The decrease in the efficiency of the clearance systems in aging, as well as the presence of genetic mutations of proteins associated with cellular proteostasis in the familial forms of TDP-43 proteinopathies, suggest that a failure of these protein degradation systems is a key factor in the aetiology of TDP-43 associated disorders. Here we show that the internalization of human pre-formed TDP-43 aggregates in the murine neuroblastoma N2a cells promptly resulted in their ubiquitination and hyperphosphorylation by endogenous machineries, mimicking the post-translational modifications observed in patients. Moreover, our data identify mitochondria as the main responsible sites for the alteration of calcium homeostasis induced by TDP-43 aggregates, which, in turn, stimulates an increase in reactive oxygen species and, finally, caspase activation. The inhibition of TDP-43 proteostasis in the presence of selective inhibitors against the proteasome and macroautophagy systems revealed that these two systems are both severely involved in TDP-43 accumulation and have a strong influence on each other in neurodegenerative disorders associated with TDP-43.

scholarly journals Ceramide Metabolism Balance, a Multifaceted Factor in Critical Steps of Breast Cancer Development

2018 ◽  
Vol 19 (9) ◽  
pp. 2527 ◽  
Author(s):  
Victor García-González ◽  
José Díaz-Villanueva ◽  
Octavio Galindo-Hernández ◽  
Israel Martínez-Navarro ◽  
Gustavo Hurtado-Ureta ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Chemotherapy Resistance ◽  
Cell Communication ◽  
Low Grade ◽  
Cancer Disease ◽  
Cellular Processes ◽  
Neoplastic Processes ◽  
Key Factor ◽  
Inflammatory State

Ceramides are key lipids in energetic-metabolic pathways and signaling cascades, modulating critical physiological functions in cells. While synthesis of ceramides is performed in endoplasmic reticulum (ER), which is altered under overnutrition conditions, proteins associated with ceramide metabolism are located on membrane arrangement of mitochondria and ER (MAMs). However, ceramide accumulation in meta-inflammation, condition that associates obesity with a chronic low-grade inflammatory state, favors the deregulation of pathways such as insulin signaling, and induces structural rearrangements on mitochondrial membrane, modifying its permeability and altering the flux of ions and other molecules. Considering the wide biological processes in which sphingolipids are implicated, they have been associated with diseases that present abnormalities in their energetic metabolism, such as breast cancer. In this sense, sphingolipids could modulate various cell features, such as growth, proliferation, survival, senescence, and apoptosis in cancer progression; moreover, ceramide metabolism is associated to chemotherapy resistance, and regulation of metastasis. Cell–cell communication mediated by exosomes and lipoproteins has become relevant in the transport of several sphingolipids. Therefore, in this work we performed a comprehensive analysis of the state of the art about the multifaceted roles of ceramides, specifically the deregulation of ceramide metabolism pathways, being a key factor that could modulate neoplastic processes development. Under specific conditions, sphingolipids perform important functions in several cellular processes, and depending on the preponderant species and cellular and/or tissue status can inhibit or promote the development of metabolic and potentially breast cancer disease.

scholarly journals Rapid in vivo measurement of β-amyloid reveals biphasic clearance kinetics in an Alzheimer’s mouse model

2016 ◽  
Vol 213 (5) ◽  
pp. 677-685 ◽  
Author(s):  
Carla M. Yuede ◽  
Hyo Lee ◽  
Jessica L. Restivo ◽  
Todd A. Davis ◽  
Jane C. Hettinger ◽  
...  
Keyword(s):  
Human Studies ◽  
In Vivo Measurement ◽  
Significant Prolongation ◽  
Secretase Inhibitor ◽  
Electrochemical Approach ◽  
Key Factor ◽  
Β Amyloid ◽  
Aβ Clearance ◽  
Clearance Kinetics

Findings from genetic, animal model, and human studies support the observation that accumulation of the β-amyloid (Aβ) peptide in the brain plays a central role in the pathogenic cascade of Alzheimer’s disease (AD). Human studies suggest that one key factor leading to accumulation is a defect in brain Aβ clearance. We have developed a novel microimmunoelectrode (MIE) to study the kinetics of Aβ clearance using an electrochemical approach. This is the first study using MIEs in vivo to measure rapid changes in Aβ levels in the brains of living mice. Extracellular, interstitial fluid (ISF) Aβ levels were measured in the hippocampus of APP/PS1 mice. Baseline levels of Aβ40 in the ISF are relatively stable and begin to decline within minutes of blocking Aβ production with a γ-secretase inhibitor. Pretreatment with a P-glycoprotein inhibitor, which blocks blood–brain barrier transport of Aβ, resulted in significant prolongation of Aβ40 half-life, but only in the latter phase of Aβ clearance from the ISF.

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