scholarly journals TheGinkgo bilobaExtract EGb 761 Modulates Proteasome Activity and Polyglutamine Protein Aggregation

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Marcel Stark ◽  
Christian Behl
Keyword(s):  
Protein Degradation ◽  
Cultured Cells ◽  
Protein Aggregates ◽  
Proteasome Activity ◽  
Protein Homeostasis ◽  
Cellular Model ◽  
Egb 761 ◽  
Polyq Protein ◽  
Polyglutamine Protein ◽  
Potential Use

The standardizedGinkgo bilobaextract EGb 761 has well-described antioxidative activities and effects on different cytoprotective signaling pathways. Consequently, a potential use of EGb 761 in neurodegenerative diseases has been proposed. A common characteristic feature of a variety of such disorders is the pathologic formation of protein aggregates, suggesting a crucial role for protein homeostasis. In this study, we show that EGb 761 increased the catalytic activity of the proteasome and enhanced protein degradation in cultured cells. We further investigated this effect in a cellular model of Huntington’s disease (HD) by employing cells expressing pathologic variants of a polyglutamine protein (polyQ protein). We show that EGb 761 affected these cells by (i) increasing proteasome activity and (ii) inducing a more efficient degradation of aggregation-prone proteins. These results demonstrate a novel activity of EGb 761 on protein aggregates by enhancing proteasomal protein degradation, suggesting a therapeutic use in neurodegenerative disorders with a disturbed protein homeostasis.

scholarly journals Tissue-specific downregulation of EDTP suppresses polyglutamine protein aggregates and extends lifespan in Drosophila

2017 ◽  
Author(s):  
Chengfeng Xiao ◽  
Shuang Qiu ◽  
R Meldrum Robertson ◽  
Laurent Seroude
Keyword(s):  
Glial Cells ◽  
Genetic Disorder ◽  
Tyrosine Phosphatase ◽  
Protein Aggregates ◽  
Protein Aggregate ◽  
Tissue Specific ◽  
Lipid Phosphatase ◽  
Muscle Tissues ◽  
Polyq Protein ◽  
Polyglutamine Protein

ABSTRACTDrosophila egg-derived tyrosine phosphatase (EDTP, also called JUMPY) is a lipid phosphatase essential in oogenesis and muscle function in the adult stage. Although mammalian JUMPY negatively regulates autophagy, loss-of-JUMPY causes muscle dysfunction and is associated with a rare genetic disorder called centronuclear myopathy. Here we show that tissue-specific downregulation of EDTP in Drosophila non-muscle tissues, particularly glial cells, suppresses the expression of polyglutamine (polyQ) protein aggregates in the same cells and improves survival. Additionally, tissue-specific downregulation of EDTP in glial cells or motoneurons extends lifespan. We demonstrate an approach to fine-tune the expression of a disease-associated gene EDTP for the removal of polyQ protein aggregate and lifespan extension in Drosophila.

scholarly journals Compromising the 19S proteasome complex protects cells from reduced flux through the proteasome

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Peter Tsvetkov ◽  
Marc L Mendillo ◽  
Jinghui Zhao ◽  
Jan E Carette ◽  
Parker H Merrill ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Cellular Protein ◽  
Fitness Cost ◽  
Survival Advantage ◽  
Protein Homeostasis ◽  
Proteotoxic Stress ◽  
Genome Wide ◽  
Regulatory Complex ◽  
Modest Reduction ◽  
Specific Inhibitors

Proteasomes are central regulators of protein homeostasis in eukaryotes. Proteasome function is vulnerable to environmental insults, cellular protein imbalance and targeted pharmaceuticals. Yet, mechanisms that cells deploy to counteract inhibition of this central regulator are little understood. To find such mechanisms, we reduced flux through the proteasome to the point of toxicity with specific inhibitors and performed genome-wide screens for mutations that allowed cells to survive. Counter to expectation, reducing expression of individual subunits of the proteasome's 19S regulatory complex increased survival. Strong 19S reduction was cytotoxic but modest reduction protected cells from inhibitors. Protection was accompanied by an increased ratio of 20S to 26S proteasomes, preservation of protein degradation capacity and reduced proteotoxic stress. While compromise of 19S function can have a fitness cost under basal conditions, it provided a powerful survival advantage when proteasome function was impaired. This means of rebalancing proteostasis is conserved from yeast to humans.

scholarly journals Substrate-Specific Effects of Natural Genetic Variation on Proteasome Activity

2021 ◽  
Author(s):  
Mahlon Collins ◽  
Randi R. Avery ◽  
Frank W Albert
Keyword(s):  
Genetic Variation ◽  
Protein Degradation ◽  
Dynamic Control ◽  
Cellular Protein ◽  
Proteasome Activity ◽  
Heritable Variation ◽  
Natural Genetic Variation ◽  
Specific Effects ◽  
Regulatory Particle

The bulk of targeted cellular protein degradation is performed by the proteasome, a multi-subunit complex consisting of the 19S regulatory particle, which binds, unfolds, and translocates substrate proteins, and the 20S core particle, which degrades them. Protein homeostasis requires precise, dynamic control of proteasome activity. To what extent genetic variation creates differences in proteasome activity is almost entirely unknown. Using the ubiquitin-independent degrons of the ornithine decarboxylase and Rpn4 proteins, we developed reporters that provide high-throughput, quantitative measurements of proteasome activity in vivo in genetically diverse cell populations. We used these reporters to characterize the genetic basis of variation in proteasome activity in the yeast Saccharomyces cerevisiae. We found that proteasome activity is a complex, polygenic trait, shaped by variation throughout the genome. Genetic influences on proteasome activity were predominantly substrate-specific, suggesting that they primarily affect the function or activity of the 19S regulatory particle. Our results demonstrate that individual genetic differences create heritable variation in proteasome activity and suggest that genetic effects on proteasomal protein degradation may be an important source of variation in cellular and organismal traits.

Abstract 37: Centrosome Destabilization Through the Ubiquitin-Proteasome Pathway Regulates Proplatelet Production

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Kellie R Machlus ◽  
Prakrith Vijey ◽  
Thomas Soussou ◽  
Joseph E Italiano
Keyword(s):  
Protein Degradation ◽  
Proteasome Inhibitors ◽  
Aurora Kinase ◽  
Proteasome Activity ◽  
Major Pathway ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Proplatelet Formation

Background: Proteasome inhibitors such as bortezomib, a chemotherapeutic used to treat multiple myeloma, induce thrombocytopenia within days of initiation. The mechanism for this thrombocytopenia has been tied to data revealing that proteasome activity is essential for platelet formation. The major pathway of selective protein degradation uses ubiquitin as a marker that targets proteins for proteolysis by the proteasome. This pathway is previously unexplored in megakaryocytes (MKs). Objectives: We aim to define the mechanism by which the ubiquitin-proteasome pathway affects MK maturation and platelet production. Results: Pharmacologic inhibition of proteasome activity blocks proplatelet formation in megakaryocytes. To further characterize how this degradation was occurring, we probed distinct ubiquitin pathways. Inhibition of the ubiquitin-activating enzyme E1 significantly inhibited proplatelet formation up to 73%. In addition, inhibition of the deubiquitinase proteins UCHL5 and USP14 significantly inhibited proplatelet formation up to 83%. These data suggest that an intact ubiquitin pathway is necessary for proplatelet formation. Proteomic and polysome analyses of MKs undergoing proplatelet formation revealed a subset of proteins decreased in proplatelet-producing megakaryocytes, consistent with data showing that protein degradation is necessary for proplatelet formation. Specifically, the centrosome stabilizing proteins Aurora kinase (Aurk) A/B, Tpx2, Cdk1, and Plk1 were decreased in proplatelet-producing MKs. Furthermore, inhibition of AurkA and Plk1, but not Cdk1, significantly inhibited proplatelet formation in vitro over 83%. Conclusions: We hypothesize that proplatelet formation is triggered by centrosome destabilization and disassembly, and that the ubiquitin-proteasome pathway plays a crucial role in this transformation. Specifically, regulation of the AurkA/Plk1/Tpx2 pathway may be key in centrosome integrity and initiation of proplatelet formation. Determination of the mechanism by which the ubiquitin-proteasome pathway regulates the centrosome and facilitates proplatelet formation will allow us to design better strategies to target and reverse thrombocytopenia.

scholarly journals Human tauopathy-derived tau strains determine the substrates recruited for templated amplification

Brain ◽  
2021 ◽  
Author(s):  
Airi Tarutani ◽  
Haruka Miyata ◽  
Takashi Nonaka ◽  
Kazuko Hasegawa ◽  
Mari Yoshida ◽  
...  
Keyword(s):  
Cultured Cells ◽  
Corticobasal Degeneration ◽  
Biochemical Properties ◽  
Cellular Model ◽  
Cryo Electron Microscopy ◽  
Structural Differences ◽  
The Brain ◽  
Strain Dependent ◽  
Disease Specific ◽  
Prion Hypothesis

Abstract Tauopathies are a subset of neurodegenerative diseases characterized by abnormal tau inclusions. Specifically, three-repeat tau and four-repeat tau in Alzheimer’s disease (AD), three-repeat tau in Pick's disease (PiD) and four-repeat in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) form amyloid-like fibrous structures that accumulate in neurons and/or glial cells. Amplification and cell-to-cell transmission of abnormal tau based on the prion hypothesis are believed to explain the onset and progression of tauopathies. Recent studies support not only the self-propagation of abnormal tau, but also the presence of conformationally distinct tau aggregates, namely tau strains. Cryo-electron microscopy analyses of patient-derived tau filaments have revealed disease-specific ordered tau structures. However, it remains unclear whether the ultrastructural and biochemical properties of tau strains are inherited during the amplification of abnormal tau in the brain. In this study, we investigated template-dependent amplification of tau aggregates using a cellular model of seeded aggregation. Tau strains extracted from human tauopathies caused strain-dependent accumulation of insoluble filamentous tau in SH-SY5Y cells. The seeding activity towards full-length four-repeat tau substrate was highest in CBD-tau seeds, followed by PSP-tau and AD-tau seeds, while AD-tau seeds showed higher seeding activity than PiD-tau seeds towards three-repeat tau substrates. Abnormal tau amplified in cells inherited the ultrastructural and biochemical properties of the original seeds. These results strongly suggest that the structural differences of patient-derived tau strains underlie the diversity of tauopathies, and that seeded aggregation and filament formation mimicking the pathogenesis of sporadic tauopathy can be reproduced in cultured cells. Our results indicate that the disease-specific conformation of tau aggregates determines the tau isoform substrate that is recruited for templated amplification, and also influences the prion-like seeding activity.

scholarly journals Effects of liver regeneration on tRNA contents and aminoacyl-tRNA synthetase activities and sedimentation patterns

1986 ◽  
Vol 236 (1) ◽  
pp. 163-169 ◽  
Author(s):  
U Del Monte ◽  
S Capaccioli ◽  
G Neri Cini ◽  
R Perego ◽  
R Caldini ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Cultured Cells ◽  
Trna Synthetase ◽  
Synthetase Activity ◽  
Regenerating Liver ◽  
Trna Synthetases ◽  
Aminoacyl Trna Synthetases ◽  
Acceptor Capacity ◽  
Increased Activity

The tRNA content and aminoacyl-tRNA synthetases of regenerating liver in the phase of rapid growth were compared with those of livers from both intact and sham-operated rats. At 48 h after hepatectomy, the amount of active tRNA (called ‘total acceptor capacity’) is significantly higher in regenerating liver than in control livers, owing to a general, possibly not uniform, increase in the various tRNA families, which suggests that it may contribute to the increased protein synthesis and to decreased protein degradation as well. The activities of most, but not of all, aminoacyl-tRNA synthetases in cell sap of regenerating liver tend to be greater than normal. Increased activity of histidyl-tRNA synthetase fits in with the possibility that the mechanisms that control the rate of protein degradation through aminoacylation of tRNAHis in cultured cells [Scornik (1983) J. Biol. Chem. 258, 882-886] also operate in the liver and play a role in regeneration. Sedimentation analysis of cell sap in sucrose density gradients shows a shift of prolyl-tRNA synthetase activity toward the high-Mr form in regenerating liver. This change might be related to the positive protein balance and to growth in vivo, since it is also observed in the anaplastic Yoshida ascites hepatoma AH 130.

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