scholarly journals Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders

Antioxidants ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 1483
Author(s):  
Doris Loh ◽  
Russel J. Reiter
Keyword(s):  
Phase Separation ◽  
Neurodegenerative Disorders ◽  
Protein Trafficking ◽  
Rna Binding ◽  
Membrane Lipids ◽  
Protein Composition ◽  
Line Tension ◽  
Membrane Lipid ◽  
Membrane Curvature ◽  
Raft Domains

Biomolecular condensates are membraneless organelles (MLOs) that form dynamic, chemically distinct subcellular compartments organizing macromolecules such as proteins, RNA, and DNA in unicellular prokaryotic bacteria and complex eukaryotic cells. Separated from surrounding environments, MLOs in the nucleoplasm, cytoplasm, and mitochondria assemble by liquid–liquid phase separation (LLPS) into transient, non-static, liquid-like droplets that regulate essential molecular functions. LLPS is primarily controlled by post-translational modifications (PTMs) that fine-tune the balance between attractive and repulsive charge states and/or binding motifs of proteins. Aberrant phase separation due to dysregulated membrane lipid rafts and/or PTMs, as well as the absence of adequate hydrotropic small molecules such as ATP, or the presence of specific RNA proteins can cause pathological protein aggregation in neurodegenerative disorders. Melatonin may exert a dominant influence over phase separation in biomolecular condensates by optimizing membrane and MLO interdependent reactions through stabilizing lipid raft domains, reducing line tension, and maintaining negative membrane curvature and fluidity. As a potent antioxidant, melatonin protects cardiolipin and other membrane lipids from peroxidation cascades, supporting protein trafficking, signaling, ion channel activities, and ATPase functionality during condensate coacervation or dissolution. Melatonin may even control condensate LLPS through PTM and balance mRNA- and RNA-binding protein composition by regulating N6-methyladenosine (m6A) modifications. There is currently a lack of pharmaceuticals targeting neurodegenerative disorders via the regulation of phase separation. The potential of melatonin in the modulation of biomolecular condensate in the attenuation of aberrant condensate aggregation in neurodegenerative disorders is discussed in this review.

scholarly journals Disease-linked TDP-43 hyperphosphorylation suppresses TDP-43 condensation and aggregation

2021 ◽  
Author(s):  
Lara Gruijs da Silva ◽  
Francesca Simonetti ◽  
Saskia Hutten ◽  
Henrick Riemenschneider ◽  
Erin L. Sternburg ◽  
...  
Keyword(s):  
Phase Separation ◽  
Neurodegenerative Disorders ◽  
Nuclear Import ◽  
Cellular Response ◽  
Rna Binding ◽  
Low Complexity ◽  
Post Translational Modifications ◽  
Multi Scale ◽  
Regulatory Functions ◽  
Lateral Sclerosis

AbstractPost-translational modifications (PTMs) have emerged as key modulators of protein phase separation and have been linked to protein aggregation in neurodegenerative disorders. The major aggregating protein in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), the RNA-binding protein TDP-43, is hyperphosphorylated in disease on several C-terminal serine residues, which is generally believed to promote TDP-43 aggregation. Here, we show that hyperphosphorylation by Casein kinase 1δ or C-terminal phosphomimetic mutations surprisingly reduce TDP-43 phase separation and aggregation and render TDP-43 condensates more liquid-like and dynamic. Multi-scale simulations reveal reduced homotypic interactions of TDP-43 low complexity domains through enhanced solvation of phosphomimetic residues. Cellular experiments show that phosphomimetic substitutions do not affect nuclear import or RNA regulatory functions of TDP-43, but suppress accumulation of TDP-43 in membrane-less organelles and promote its solubility in neurons. We propose that TDP-43 hyperphosphorylation may be a protective cellular response to counteract TDP-43 aggregation.

scholarly journals Effect of Vesicle Size on the Cytolysis of Cell-Penetrating Peptides (CPPs)

2020 ◽  
Vol 21 (19) ◽  
pp. 7405
Author(s):  
Kazutami Sakamoto ◽  
Takeshi Kitano ◽  
Haruka Kuwahara ◽  
Megumi Tedani ◽  
Kenichi Aburai ◽  
...  
Keyword(s):  
Phase Transfer ◽  
Membrane Lipids ◽  
Positive Curvature ◽  
Membrane Lipid ◽  
Cell Penetrating Peptides ◽  
Membrane Curvature ◽  
Local Phase ◽  
Vesicle Size ◽  
Cell Penetrating ◽  
A Cell

A specific series of peptides, called a cell-penetrating peptide (CPP), is known to be free to directly permeate through cell membranes into the cytosol (cytolysis); hence, this CPP would be a potent carrier for a drug delivery system (DDS). Previously, we proposed the mechanism of cytolysis as a temporal and local phase transfer of membrane lipid caused by positive membrane curvature generation. Moreover, we showed how to control the CPP cytolysis. Here, we investigate the phospholipid vesicle’s size effect on CPP cytolysis because this is the most straightforward way to control membrane curvature. Contrary to our expectation, we found that the smaller the vesicle diameter (meaning a higher membrane curvature), the more cytolysis was suppressed. Such controversial findings led us to seek the reason for the unexpected results, and we ended up finding out that the mobility of membrane lipids as a liquid crystal is the key to cytolysis. As a result, we could explain the cause of cytolysis suppression by reducing the vesicle size (because of the restriction of lipid mobility); osmotic pressure reduction to enhance positive curvature generation works as long as the membrane is mobile enough to modulate the local structure. Taking all the revealed vital factors and their effects as a tool, we will further explore how to control CPP cytolysis for developing a DDS system combined with appropriate cargo selection to be tagged with CPPs.

scholarly journals Cavin1 intrinsically disordered domains are essential for fuzzy electrostatic interactions and caveola formation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Vikas A. Tillu ◽  
James Rae ◽  
Ya Gao ◽  
Nicholas Ariotti ◽  
Matthias Floetenmeyer ◽  
...  
Keyword(s):  
Electrostatic Interactions ◽  
Membrane Lipid ◽  
Membrane Curvature ◽  
Caveolin 1 ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Solution Generation ◽  
Endosomal System ◽  
Disordered Regions

AbstractCaveolae are spherically shaped nanodomains of the plasma membrane, generated by cooperative assembly of caveolin and cavin proteins. Cavins are cytosolic peripheral membrane proteins with negatively charged intrinsically disordered regions that flank positively charged α-helical regions. Here, we show that the three disordered domains of Cavin1 are essential for caveola formation and dynamic trafficking of caveolae. Electrostatic interactions between disordered regions and α-helical regions promote liquid-liquid phase separation behaviour of Cavin1 in vitro, assembly of Cavin1 oligomers in solution, generation of membrane curvature, association with caveolin-1, and Cavin1 recruitment to caveolae in cells. Removal of the first disordered region causes irreversible gel formation in vitro and results in aberrant caveola trafficking through the endosomal system. We propose a model for caveola assembly whereby fuzzy electrostatic interactions between Cavin1 and caveolin-1 proteins, combined with membrane lipid interactions, are required to generate membrane curvature and a metastable caveola coat.

scholarly journals Lipid Remodeling Confers Osmotic Stress Tolerance to Embryogenic Cells during Cryopreservation

2021 ◽  
Vol 22 (4) ◽  
pp. 2174
Author(s):  
Liang Lin ◽  
Junchao Ma ◽  
Qin Ai ◽  
Hugh W. Pritchard ◽  
Weiqi Li ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Technology Development ◽  
Membrane Lipids ◽  
Species Conservation ◽  
Membrane Lipid ◽  
Cell Integrity ◽  
Embryogenic Cells ◽  
Osmotic Stress Tolerance ◽  
Lipid Species ◽  
Magnolia Officinalis

Plant species conservation through cryopreservation using plant vitrification solutions (PVS) is based in empiricism and the mechanisms that confer cell integrity are not well understood. Using ESI-MS/MS analysis and quantification, we generated 12 comparative lipidomics datasets for membranes of embryogenic cells (ECs) of Magnolia officinalis during cryogenic treatments. Each step of the complex PVS-based cryoprotocol had a profoundly different impact on membrane lipid composition. Loading treatment (osmoprotection) remodeled the cell membrane by lipid turnover, between increased phosphatidic acid (PA) and phosphatidylglycerol (PG) and decreased phosphatidylcholine (PC) and phosphatidylethanolamine (PE). The PA increase likely serves as an intermediate for adjustments in lipid metabolism to desiccation stress. Following PVS treatment, lipid levels increased, including PC and PE, and this effectively counteracted the potential for massive loss of lipid species when cryopreservation was implemented in the absence of cryoprotection. The present detailed cryobiotechnology findings suggest that the remodeling of membrane lipids and attenuation of lipid degradation are critical for the successful use of PVS. As lipid metabolism and composition varies with species, these new insights provide a framework for technology development for the preservation of other species at increasing risk of extinction.

scholarly journals The SARS-CoV-2 nucleocapsid phosphoprotein forms mutually exclusive condensates with RNA and the membrane-associated M protein

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Shan Lu ◽  
Qiaozhen Ye ◽  
Digvijay Singh ◽  
Yong Cao ◽  
Jolene K. Diedrich ◽  
...  
Keyword(s):  
Phase Separation ◽  
Potential Role ◽  
Rna Binding ◽  
Stress Granule ◽  
M Protein ◽  
Rich Region ◽  
Virion Assembly ◽  
N Protein ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions

AbstractThe multifunctional nucleocapsid (N) protein in SARS-CoV-2 binds the ~30 kb viral RNA genome to aid its packaging into the 80–90 nm membrane-enveloped virion. The N protein is composed of N-terminal RNA-binding and C-terminal dimerization domains that are flanked by three intrinsically disordered regions. Here we demonstrate that the N protein’s central disordered domain drives phase separation with RNA, and that phosphorylation of an adjacent serine/arginine rich region modulates the physical properties of the resulting condensates. In cells, N forms condensates that recruit the stress granule protein G3BP1, highlighting a potential role for N in G3BP1 sequestration and stress granule inhibition. The SARS-CoV-2 membrane (M) protein independently induces N protein phase separation, and three-component mixtures of N + M + RNA form condensates with mutually exclusive compartments containing N + M or N + RNA, including annular structures in which the M protein coats the outside of an N + RNA condensate. These findings support a model in which phase separation of the SARS-CoV-2 N protein contributes both to suppression of the G3BP1-dependent host immune response and to packaging genomic RNA during virion assembly.

scholarly journals Impact of Membrane Lipids on UapA and AzgA Transporter Subcellular Localization and Activity in Aspergillus nidulans

2021 ◽  
Vol 7 (7) ◽  
pp. 514
Author(s):  
Mariangela Dionysopoulou ◽  
George Diallinas
Keyword(s):  
Plasma Membrane ◽  
Subcellular Localization ◽  
Aspergillus Nidulans ◽  
Membrane Lipids ◽  
Membrane Lipid ◽  
Lipid Biosynthesis ◽  
Transport Kinetics ◽  
Negative Effect ◽  
And Function

Recent biochemical and biophysical evidence have established that membrane lipids, namely phospholipids, sphingolipids and sterols, are critical for the function of eukaryotic plasma membrane transporters. Here, we study the effect of selected membrane lipid biosynthesis mutations and of the ergosterol-related antifungal itraconazole on the subcellular localization, stability and transport kinetics of two well-studied purine transporters, UapA and AzgA, in Aspergillus nidulans. We show that genetic reduction in biosynthesis of ergosterol, sphingolipids or phosphoinositides arrest A. nidulans growth after germling formation, but solely blocks in early steps of ergosterol (Erg11) or sphingolipid (BasA) synthesis have a negative effect on plasma membrane (PM) localization and stability of transporters before growth arrest. Surprisingly, the fraction of UapA or AzgA that reaches the PM in lipid biosynthesis mutants is shown to conserve normal apparent transport kinetics. We further show that turnover of UapA, which is the transporter mostly sensitive to membrane lipid content modification, occurs during its trafficking and by enhanced endocytosis, and is partly dependent on autophagy and Hect-type HulARsp5 ubiquitination. Our results point out that the role of specific membrane lipids on transporter biogenesis and function in vivo is complex, combinatorial and transporter-dependent.

Phase separation of RNA-binding protein promotes polymerase binding and transcription

2021 ◽  
Author(s):  
Wen Shao ◽  
Xianju Bi ◽  
Yixuan Pan ◽  
Boyang Gao ◽  
Jun Wu ◽  
...  
Keyword(s):  
Phase Separation ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Polymerase Binding

Membrane Lipids and Maximum Lifespan in Clownfish

2021 ◽  
Author(s):  
PEDRO FRANCISCO ALMAIDA PAGÁN ◽  
Alejandro Lucas-Sanchez ◽  
Antonio Martinez-Nicolas ◽  
Eva Terzibasi ◽  
Maria Angeles Rol de Lama ◽  
...  
Keyword(s):  
Lipid Composition ◽  
Potential Model ◽  
Membrane Lipids ◽  
Membrane Lipid ◽  
Maximum Lifespan ◽  
Homeoviscous Adaptation ◽  
Theory Of Aging ◽  
Peroxidation Index ◽  
Membrane Peroxidation ◽  
Contradictory Data

Abstract The longevity-homeoviscous adaptation (LHA) theory of aging states that lipid composition of cell membranes is linked to metabolic rate and lifespan, which has been widely shown in mammals and birds but not sufficiently in fish. In this study, two species of the genus Amphiprion (A. percula and A. clarkii, with estimated maximum lifespan potentials [MLSP] of 30 and 9-16 years, respectively) and the damselfish Chromis viridis (estimated MLSP of 1-2 years) were chosen to test the LHA theory of aging in a potential model of exceptional longevity. Brain, livers and samples of skeletal muscle were collected for lipid analyses and integral part in the computation of membrane peroxidation indexes (PIn) from phospholipid (PL) fractions and PL fatty acid composition. When only the two anemonefish were compared, results pointed to the existence of a negative correlation between membrane PIn value and maximum life expectancy, well in line with the predictions from the LHA theory of aging. Nevertheless, contradictory data were obtained when the two clownfish were compared to the shorter-lived C. viridis. This results along with those obtained in previous studies on fish denote that the magnitude (and sometimes the direction) of the differences observed in membrane lipid composition and peroxidation index with MLSP cannot explain alone the diversity in longevity found among fishes.

scholarly journals Association of the Yeast RNA-binding Protein She2p with the Tubular Endoplasmic Reticulum Depends on Membrane Curvature

2013 ◽  
Vol 288 (45) ◽  
pp. 32384-32393 ◽  
Author(s):  
Christian Genz ◽  
Julia Fundakowski ◽  
Orit Hermesh ◽  
Maria Schmid ◽  
Ralf-Peter Jansen
Keyword(s):  
Endoplasmic Reticulum ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Membrane Curvature ◽  
Tubular Endoplasmic Reticulum

scholarly journals Responses of Unsaturated Fatty Acid in Membrane Lipid and Antioxidant Enzymes to Chilling Stress in Sweet Sorghum (Sorghum bicolor (L.) Moench) Seedling

2016 ◽  
Vol 8 (9) ◽  
pp. 71 ◽  
Author(s):  
Yuanyuan Guo ◽  
Shanshan Liu ◽  
Zhen Yang ◽  
Shanshan Tian ◽  
Na Sui
Keyword(s):  
Antioxidant Enzymes ◽  
Fatty Acid ◽  
Sorghum Bicolor ◽  
Unsaturated Fatty Acid ◽  
Sweet Sorghum ◽  
Membrane Lipids ◽  
Chilling Stress ◽  
Fatty Acid Content ◽  
Membrane Lipid ◽  
Protective Enzyme

<p>Low temperature is a major factor limiting the productivity and geographical distribution of many plant species. In this study, we investigated the effect of chilling stress (10 <sup>o</sup>C) on seedling growth in two sweet sorghum (<em>Sorghum bicolor </em>(L.) Moench) inbred lines (M-81E and Roma). Results showed that the chilling resistance of M-81E was higher than that of Roma. The Fv/Fm in leaves of M-81E decreased less than that of Roma during chilling stress. After 24 h of chilling stress, the Fv/Fm of M-81E and Roma decreased by 24.3 and 45.8%, respectively. Fo was also affected significantly during chilling stress. Malondialdehyde (MDA), an indicator of lipid peroxidation caused by ROS, increased during chilling stress. The contents of MDA increased less in leaves of M-81E than that in Roma under chilling stress. The antioxidant enzymes (SOD and APX) activity of M-81E was higher than those of Roma during chilling stress. The unsaturated fatty acid content and the double bond index (DBI) of major membrane lipids of MGDG, DGDG, SQDG, PC, PE and PG of M-81E significantly increased after 24 h of chilling treatment (10 <sup>o</sup>C). The DBI of MGDG, DGDG, SQDG, PC and PG of Roma significantly decreased. These results showed that the chilling tolerance of M-81E was higher than that of Roma by increasing of unsaturated fatty acid in membrane lipid and powerful protective enzyme system at seedling stage.</p>

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