The aggravating role of the ubiquitin–proteasome system in neurodegenerative disease

2006 ◽  
Vol 34 (5) ◽  
pp. 743-745 ◽  
Author(s):  
C.-C. Hung ◽  
E.J. Davison ◽  
P.A. Robinson ◽  
H.C. Ardley
Keyword(s):  
Ubiquitin Proteasome System ◽  
Model Systems ◽  
Protective Mechanism ◽  
Ubiquitinated Proteins ◽  
Age Related ◽  
Ubiquitin Proteasome ◽  
Vitro Model ◽  
Novel Therapeutic Strategies

Intraneuronal inclusion bodies are key pathological features of most age-related neurodegenerative disorders including Parkinson's disease and Alzheimer's disease. These inclusions are commonly characterized both by the presence of ubiquitinated proteins and the sequestration of components of the UPS (ubiquitin–proteasome system). Unfortunately, as we age, the efficiency of the UPS declines, suggesting that the presence of ubiquitinated proteins and UPS components in inclusions may reflect unsuccessful attempts by the (failing) UPS to remove the aggregating proteins. Whether the physical presence of inclusions causes cell death or, conversely, whether they are non-toxic and their presence reflects a cellular protective mechanism remains highly controversial. Animal and in vitro model systems that allow detailed characterization of the inclusions and their effects on the cell have been developed by us and others. Identification of the mechanisms involved in inclusion formation is already aiding the development of novel therapeutic strategies to prevent or alleviate aggregate-associated neurodegenerative diseases.

scholarly journals Neuroprotective Role of Camel α-Lactalbumin Via Regulating SIRT1/FOXO3a Pathway Against Rotenone-Induced Neurotoxicity

2021 ◽  
Author(s):  
Saba Ubaid ◽  
Shivani Pandey ◽  
Mohd. Sohail Akhtar ◽  
Mohammad Rumman ◽  
Babita Singh ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Ubiquitin Proteasome System ◽  
Protective Agent ◽  
Brain Disorder ◽  
Current Therapies ◽  
Ubiquitin Proteasome ◽  
Potential Activity ◽  
Apoptotic Pathways

Abstract Camel milk is rich in nutritional factors, such as α- Lactalbumin, and important for brain development. It is known to act as a potential therapeutic candidate for brain disorder via regulation of inflammatory and apoptotic pathways. Mechanisms that are critically involved with Parkinson’s disease (PD) are apoptosis, inflammation, and oxidative stress, and the aberrated ubiquitin-proteasome system. Adverse effects of current therapies are imposing the need for the development of natural neuroprotective agents that are very effective and have fewer or no side effects. The present study aimed to evaluate the potential activity of camel α-Lactalbumin (α-LA) in rotenone induced in-vitro PD model. In this study, we hypothesized the use of camel α-lactalbumin as an effective curative agent for PD. The mechanism of action of camel α-lactalbumin was investigated by assessing the effect of α-LA on the level of nitric oxide, NADH, MMP9, inflammatory markers, and on the expression level of SIRT1 and FOXO3a in SH-SY5Y cell line. Overall, the results revealed the potent neuroprotective efficacy of α-Lactalbumin in rotenone-induced PD model via effectively modulating apoptotic pathways, oxidative stress, and neuroinflammatory cascades. Conclusively, these findings confirmed that α-LA could be a biologically effective protective agent against rotenone induced neurotoxic impacts and neurobehavioral aberrations.

scholarly journals Neurodevelopmental Disorders (NDD) Caused by Genomic Alterations of the Ubiquitin-Proteasome System (UPS): the Possible Contribution of Immune Dysregulation to Disease Pathogenesis

2021 ◽  
Vol 14 ◽  
Author(s):  
Frédéric Ebstein ◽  
Sébastien Küry ◽  
Jonas Johannes Papendorf ◽  
Elke Krüger
Keyword(s):  
Neurodevelopmental Disorders ◽  
Ubiquitin Proteasome System ◽  
Immune Dysregulation ◽  
Innate Immune ◽  
Proteasome Subunits ◽  
Ubiquitin Proteasome ◽  
E2 Enzymes ◽  
Novel Therapeutic Strategies ◽  
The Brain

Over thirty years have passed since the first description of ubiquitin-positive structures in the brain of patients suffering from Alzheimer’s disease. Meanwhile, the intracellular accumulation of ubiquitin-modified insoluble protein aggregates has become an indisputable hallmark of neurodegeneration. However, the role of ubiquitin and a fortiori the ubiquitin-proteasome system (UPS) in the pathogenesis of neurodevelopmental disorders (NDD) is much less described. In this article, we review all reported monogenic forms of NDD caused by lesions in genes coding for any component of the UPS including ubiquitin-activating (E1), -conjugating (E2) enzymes, ubiquitin ligases (E3), ubiquitin hydrolases, and ubiquitin-like modifiers as well as proteasome subunits. Strikingly, our analysis revealed that a vast majority of these proteins have a described function in the negative regulation of the innate immune response. In this work, we hypothesize a possible involvement of autoinflammation in NDD pathogenesis. Herein, we discuss the parallels between immune dysregulation and neurodevelopment with the aim at improving our understanding the biology of NDD and providing knowledge required for the design of novel therapeutic strategies.

scholarly journals EOMES is responsible for WNT memory and can substitute for WNT in mesendoderm specification

2021 ◽  
Author(s):  
Anna Yoney ◽  
Lu Bai ◽  
Ali H. Brivanlou ◽  
Eric D Siggia
Keyword(s):  
Target Genes ◽  
Embryonic Stem ◽  
Model Systems ◽  
Mechanistic Basis ◽  
Vitro Model ◽  
Transcriptional Output ◽  
Accessible Chromatin ◽  
Pluripotency Maintenance

Embryogenesis is guided by a limited set of signaling pathways that are reused at different times and places throughout development. How a context dependent signaling response is generated has been a central question of developmental biology, which can now be addressed with in vitro model systems. Our previous work in human embryonic stem cells (hESCs) established that pre-exposure of cells to WNT/β-catenin signaling is sufficient to switch the output of ACTIVIN/SMAD2 signaling from pluripotency maintenance to mesendoderm (ME) differentiation. A body of previous literature has established the role of both pathways in ME differentiation. However, our work demonstrated that the two signals do not need to be present simultaneously and that hESCs have a means to record WNT signals. Here we demonstrate that hESCs have accessible chromatin at SMAD2 binding sites near pluripotency and ME-associated target genes and that WNT priming does not alter SMAD2 binding. Rather our results indicate that stable transcriptional output at ME genes results from WNT-dependent production of an additional SMAD2 co-factor, EOMES. We show that expression of EOMES can replace WNT signaling in ME differentiation, providing a mechanistic basis for WNT-priming and memory in early development.

scholarly journals The Role of Autophagy and Autophagy Receptor NDP52 in Microbial Infections

2020 ◽  
Vol 21 (6) ◽  
pp. 2008 ◽  
Author(s):  
Shuangqi Fan ◽  
Keke Wu ◽  
Mengpo Zhao ◽  
Erpeng Zhu ◽  
Shengming Ma ◽  
...  
Keyword(s):  
Ubiquitin Proteasome System ◽  
Degradation Pathway ◽  
Protective Mechanism ◽  
Pathogenic Microorganism ◽  
Microbial Infection ◽  
Selective Autophagy ◽  
Microbial Infections ◽  
Ubiquitin Proteasome ◽  
Cellular Components

Autophagy is a general protective mechanism for maintaining homeostasis in eukaryotic cells, regulating cellular metabolism, and promoting cell survival by degrading and recycling cellular components under stress conditions. The degradation pathway that is mediated by autophagy receptors is called selective autophagy, also named as xenophagy. Autophagy receptor NDP52 acts as a ‘bridge’ between autophagy and the ubiquitin-proteasome system, and it also plays an important role in the process of selective autophagy. Pathogenic microbial infections cause various diseases in both humans and animals, posing a great threat to public health. Increasing evidence has revealed that autophagy and autophagy receptors are involved in the life cycle of pathogenic microbial infections. The interaction between autophagy receptor and pathogenic microorganism not only affects the replication of these microorganisms in the host cell, but it also affects the host’s immune system. This review aims to discuss the effects of autophagy on pathogenic microbial infection and replication, and summarizes the mechanisms by which autophagy receptors interact with microorganisms. While considering the role of autophagy receptors in microbial infection, NDP52 might be a potential target for developing effective therapies to treat pathogenic microbial infections.

scholarly journals It Is All about (U)biquitin: Role of Altered Ubiquitin-Proteasome System and UCHL1 in Alzheimer Disease

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Antonella Tramutola ◽  
Fabio Di Domenico ◽  
Eugenio Barone ◽  
Marzia Perluigi ◽  
D. Allan Butterfield
Keyword(s):  
Oxidative Stress ◽  
Alzheimer Disease ◽  
Ubiquitin Proteasome System ◽  
Oxidative Modification ◽  
Age Related ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
And Function ◽  
Cellular Components

Free radical-mediated damage to macromolecules and the resulting oxidative modification of different cellular components are a common feature of aging, and this process becomes much more pronounced in age-associated pathologies, including Alzheimer disease (AD). In particular, proteins are particularly sensitive to oxidative stress-induced damage and these irreversible modifications lead to the alteration of protein structure and function. In order to maintain cell homeostasis, these oxidized/damaged proteins have to be removed in order to prevent their toxic accumulation. It is generally accepted that the age-related accumulation of “aberrant” proteins results from both the increased occurrence of damage and the decreased efficiency of degradative systems. One of the most important cellular proteolytic systems responsible for the removal of oxidized proteins in the cytosol and in the nucleus is the proteasomal system. Several studies have demonstrated the impairment of the proteasome in AD thus suggesting a direct link between accumulation of oxidized/misfolded proteins and reduction of this clearance system. In this review we discuss the impairment of the proteasome system as a consequence of oxidative stress and how this contributes to AD neuropathology. Further, we focus the attention on the oxidative modifications of a key component of the ubiquitin-proteasome pathway, UCHL1, which lead to the impairment of its activity.

scholarly journals Toxoplasma gondii UBL-UBA Shuttle Protein DSK2s Are Important for Parasite Intracellular Replication

2021 ◽  
Vol 22 (15) ◽  
pp. 7943
Author(s):  
Heng Zhang ◽  
Xu Yang ◽  
Zhu Ying ◽  
Jing Liu ◽  
Qun Liu
Keyword(s):  
Toxoplasma Gondii ◽  
Gene Knockout ◽  
Ubiquitin Proteasome System ◽  
Parasite Growth ◽  
Intracellular Replication ◽  
Ubiquitinated Proteins ◽  
Synchronous Cell ◽  
Life Threatening ◽  
Ubiquitin Proteasome

Toxoplasma gondii (T. gondii) is an important human and veterinary pathogen causing life-threatening disease in immunocompromised patients. The UBL-UBA shuttle protein family are important components of the ubiquitin–proteasome system. Here, we identified a novel UBL-UBA shuttle protein DSK2b that is charactered by an N-terminal ubiquitin-like domain (UBL) and a C-terminal ubiquitin-associated domain (UBA). DSK2b was localized in the cytoplasm and nucleus. The deletion of dsk2b did not affect the degradation of ubiquitinated proteins, parasite growth in vitro or virulence in mice. The double-gene knockout of dsk2b and its paralogs dsk2a (ΔΔdsk2adsk2b) results in a significant accumulation of ubiquitinated proteins and the asynchronous division of T. gondii. The growth of ΔΔdsk2adsk2b was significantly inhibited in vitro, while virulence in mice was not attenuated. In addition, autophagy occurred in the ΔΔdsk2adsk2b, which was speculated to degrade the accumulated ubiquitinated proteins in the parasites. Overall, DSK2b is a novel UBL-UBA shuttle protein contributing to the degradation of ubiquitinated proteins and is important for the synchronous cell division of T. gondii.

scholarly journals Hypoxia-induced alterations in the lung ubiquitin proteasome system during pulmonary hypertension pathogenesis

2018 ◽  
Vol 8 (3) ◽  
pp. 204589401878826 ◽  
Author(s):  
Brandy E. Wade ◽  
Jingru Zhao ◽  
Jing Ma ◽  
C. Michael Hart ◽  
Roy L. Sutliff
Keyword(s):  
Mass Spectrometry ◽  
Pulmonary Hypertension ◽  
Ubiquitin Proteasome System ◽  
Global Changes ◽  
Clinical Disorder ◽  
Ubiquitinated Proteins ◽  
Protein Ubiquitination ◽  
Ubiquitin Proteasome ◽  
Protein Alterations

Pulmonary hypertension (PH) is a clinical disorder characterized by sustained increases in pulmonary vascular resistance and pressure that can lead to right ventricular (RV) hypertrophy and ultimately RV failure and death. The molecular pathogenesis of PH remains incompletely defined, and existing treatments are associated with suboptimal outcomes and persistent morbidity and mortality. Reports have suggested a role for the ubiquitin proteasome system (UPS) in PH, but the extent of UPS-mediated non-proteolytic protein alterations during PH pathogenesis has not been previously defined. To further examine UPS alterations, the current study employed C57BL/6J mice exposed to normoxia or hypoxia for 3 weeks. Lung protein ubiquitination was evaluated by mass spectrometry to identify differentially ubiquitinated proteins relative to normoxic controls. Hypoxia stimulated differential ubiquitination of 198 peptides within 131 proteins ( p < 0.05). These proteins were screened to identify candidates within pathways involved in PH pathogenesis. Some 51.9% of the differentially ubiquitinated proteins were implicated in at least one known pathway contributing to PH pathogenesis, and 13% were involved in three or more PH pathways. Anxa2, App, Jak1, Lmna, Pdcd6ip, Prkch1, and Ywhah were identified as mediators in PH pathways that undergo differential ubiquitination during PH pathogenesis. To our knowledge, this is the first study to report global changes in protein ubiquitination in the lung during PH pathogenesis. These findings suggest signaling nodes that are dynamically regulated by the UPS during PH pathogenesis. Further exploration of these differentially ubiquitinated proteins and related pathways can provide new insights into the role of the UPS in PH pathogenesis.

scholarly journals The Role of Autophagy in Chemical Proteasome Inhibition Model of Retinal Degeneration

2021 ◽  
Vol 22 (14) ◽  
pp. 7271
Author(s):  
Merry Gunawan ◽  
Choonbing Low ◽  
Kurt Neo ◽  
Siawey Yeo ◽  
Candice Ho ◽  
...  
Keyword(s):  
Retinal Degeneration ◽  
Structural Integrity ◽  
Mammalian Target Of Rapamycin ◽  
Neuroblastoma Cells ◽  
Proteasome Inhibition ◽  
Ubiquitin Proteasome System ◽  
Ocular Tissue ◽  
Protective Mechanism ◽  
Ubiquitin Proteasome

We recently demonstrated that chemical proteasome inhibition induced inner retinal degeneration, supporting the pivotal roles of the ubiquitin–proteasome system in retinal structural integrity maintenance. In this study, using beclin1-heterozygous (Becn1-Het) mice with autophagic dysfunction, we tested our hypothesis that autophagy could be a compensatory retinal protective mechanism for proteasomal impairment. Despite the reduced number of autophagosome, the ocular tissue morphology and intraocular pressure were normal. Surprisingly, Becn1-Het mice experienced the same extent of retinal degeneration as was observed in wild-type mice, following an intravitreal injection of a chemical proteasome inhibitor. Similarly, these mice equally responded to other chemical insults, including endoplasmic reticulum stress inducer, N-methyl-D-aspartate, and lipopolysaccharide. Interestingly, in cultured neuroblastoma cells, we found that the mammalian target of rapamycin-independent autophagy activators, lithium chloride and rilmenidine, rescued these cells against proteasome inhibition-induced death. These results suggest that Becn1-mediated autophagy is not an effective intrinsic protective mechanism for retinal damage induced by insults, including impaired proteasomal activity; furthermore, autophagic activation beyond normal levels is required to alleviate the cytotoxic effect of proteasomal inhibition. Further studies are underway to delineate the precise roles of different forms of autophagy, and investigate the effects of their activation in rescuing retinal neurons under various pathological conditions.

scholarly journals Impairment of Proteasome Function in Podocytes Leads to CKD

2021 ◽  
Vol 32 (3) ◽  
pp. 597-613 ◽  
Author(s):  
Shin-ichi Makino ◽  
Naritoshi Shirata ◽  
Juan Alejandro Oliva Trejo ◽  
Kanae Yamamoto-Nonaka ◽  
Hiroyuki Yamada ◽  
...  
Keyword(s):  
Proteasome Inhibition ◽  
Ubiquitin Proteasome System ◽  
26S Proteasome ◽  
Regulatory Subunit ◽  
Glomerular Injury ◽  
Ubiquitinated Proteins ◽  
Autophagic Activity ◽  
Modified Proteins

BackgroundThe ubiquitin-proteasome system (UPS) and the autophagy-lysosomal system (APLS) are major intracellular degradation procedures. The importance of the APLS in podocytes is established, but the role of the UPS is not well understood.MethodsTo investigate the role of the UPS in podocytes, mice were generated that had deletion of Rpt3 (Rpt3pdKO), which encodes an essential regulatory subunit required for construction of the 26S proteasome and its deubiquitinating function.ResultsRpt3pdKO mice showed albuminuria and glomerulosclerosis, leading to CKD. Impairment of proteasome function caused accumulation of ubiquitinated proteins and of oxidative modified proteins, and it induced podocyte apoptosis. Although impairment of proteasome function normally induces autophagic activity, the number of autophagosomes was lower in podocytes of Rpt3pdKO mice than in control mice, suggesting the autophagic activity was suppressed in podocytes with impairment of proteasome function. In an in vitro study, antioxidant apocynin and autophagy activator rapamycin suppressed podocyte apoptosis induced by proteasome inhibition. Moreover, rapamycin ameliorated the glomerular injury in the Rpt3pdKO mice. The accumulation of ubiquitinated proteins and of oxidative modified proteins, which were detected in the podocytes of Rpt3pdKO mice, is a characteristic feature of aging. An aging marker was increased in the podocytes of Rpt3pdKO mice, suggesting that impairment of proteasome function promoted signs of aging in podocytes.ConclusionsImpairment of proteasome function in podocytes led to CKD, and antioxidants and autophagy activators can be therapeutic agents for age-dependent CKD.

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