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 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 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.

Proteasome activity in experimental diabetes

2006 ◽  
Vol 1 (2) ◽  
pp. 289-298 ◽  
Author(s):  
Albena Alexandrova ◽  
Lubomir Petrov ◽  
Margarita Kirkova
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Protein Oxidation ◽  
Experimental Diabetes ◽  
Diabetic Rats ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
And Oxidative Stress

AbstractNumerous studies have indicated that oxidative stress contributes to the development and progression of diabetes and other related complications. Since the ubiquitin-proteasome pathway is involved in degradation of oxidized proteins, it is to be expected that alterations in proteasome-dependent proteolysis accompany diabetes. This paper focuses on the role of the proteasome in alloxan-induced experimental diabetes. The changes in proteasomal activity and oxidative stress indices (protein oxidation and lipid peroxidation) were evaluated. The obtained results revealed increased protein oxidation and lipid peroxidation, as well as alterations in proteasomal activities in diabetic rats. Our data indicates a significant decrease in chymotryptic-like activity; increased tryptic-like activity; and unchanged post-glutamyl peptide hydrolytic-like activity. These findings suggest the presence of oxidative stress in diabetes that appears to result in changes to the ubiquitin-proteasome pathway.

scholarly journals Multiplexed Proteomic Analysis of Oxidation and Concentrations of Cerebrospinal Fluid Proteins in Alzheimer Disease

2007 ◽  
Vol 53 (4) ◽  
pp. 657-665 ◽  
Author(s):  
Minna A Korolainen ◽  
Tuula A Nyman ◽  
Paula Nyyssönen ◽  
E Samuel Hartikainen ◽  
Tuula Pirttilä
Keyword(s):  
Oxidative Stress ◽  
Cerebrospinal Fluid ◽  
Alzheimer Disease ◽  
Cognitive Decline ◽  
Oxidative Modification ◽  
Cerebrospinal Fluid Proteins ◽  
Age Related ◽  
Aging Women ◽  
Specific Proteins ◽  
Brain Specific Proteins

Abstract Background: Carbonylation is an irreversible oxidative modification of proteins that has been linked to various conditions of oxidative stress, aging, physiological disorders, and disease. Increased oxidative stress is thus also considered to play a role in the pathogenesis of age-related neurodegenerative disorders such as Alzheimer disease (AD). In addition, it has recently become evident that the response mechanisms to increased oxidative stress may depend on sex. Several oxidized carbonylated proteins have been identified in plasma and brain of AD patients by use of 2-dimensional oxyblotting. Methods: In this pilot study, we estimated the concentrations and carbonylation of the most abundant cerebrospinal fluid proteins in aging women and men, both AD patients suffering from mild dementia and individuals exhibiting no cognitive decline. Oxidized carbonylated proteins were analyzed with 2-dimensional multiplexed oxyblotting, mass spectrometry, and database searches. Results: Signals for β-trace, λ chain, and transthyretins were decreased in probable AD patients compared with controls. The only identified protein exhibiting an increased degree of carbonylation in AD patients was λ chain. The concentrations of proteins did not generally differ between men and women; however, vitamin D–binding protein, apolipoprotein A-I, and α-1-antitrypsin exhibited higher extents of carbonylation in men. Conclusions: None of the brain-specific proteins exhibited carbonylation changes in probable AD patients compared with age-matched neurological controls showing no cognitive decline. The carbonylation status of proteins differed between women and men. Two-dimensional multiplexed oxyblotting is applicable to study both the concentrations and carbonylation of cerebrospinal fluid proteins.

scholarly journals The Neuromelanin Paradox and Its Dual Role in Oxidative Stress and Neurodegeneration

Antioxidants ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 124
Author(s):  
Alexandra Moreno-García ◽  
Alejandra Kun ◽  
Miguel Calero ◽  
Olga Calero
Keyword(s):  
Oxidative Stress ◽  
Immune Response ◽  
Neurodegenerative Disorders ◽  
Normal Aging ◽  
Saturation State ◽  
Neurodegenerative Process ◽  
Age Related ◽  
Extracellular Release ◽  
Cellular Components

Aging is associated with an increasing dysfunction of key brain homeostasis mechanisms and represents the main risk factor across most neurodegenerative disorders. However, the degree of dysregulation and the affectation of specific pathways set apart normal aging from neurodegenerative disorders. In particular, the neuronal metabolism of catecholaminergic neurotransmitters appears to be a specifically sensitive pathway that is affected in different neurodegenerations. In humans, catecholaminergic neurons are characterized by an age-related accumulation of neuromelanin (NM), rendering the soma of the neurons black. This intracellular NM appears to serve as a very efficient quencher for toxic molecules. However, when a neuron degenerates, NM is released together with its load (many undegraded cellular components, transition metals, lipids, xenobiotics) contributing to initiate and worsen an eventual immune response, exacerbating the oxidative stress, ultimately leading to the neurodegenerative process. This review focuses on the analysis of the role of NM in normal aging and neurodegeneration related to its capabilities as an antioxidant and scavenging of harmful molecules, versus its involvement in oxidative stress and aberrant immune response, depending on NM saturation state and its extracellular release.

scholarly journals The Neuromelanin Paradox and its Dual Role in Oxidative Stress and Neurodegeneration

2020 ◽  
Author(s):  
Alexandra Moreno García ◽  
Alejandra Kun ◽  
Miguel Calero Lara ◽  
Olga Calero
Keyword(s):  
Oxidative Stress ◽  
Immune Response ◽  
Neurodegenerative Disorders ◽  
Normal Aging ◽  
Saturation State ◽  
Neurodegenerative Process ◽  
Age Related ◽  
Extracellular Release ◽  
Cellular Components

Aging is associated with an increasing dysfunction of key brain homeostasis mechanisms and represents the main risk factor across most neurodegenerative disorders. However, the degree of dysregulation and the affectation of specific pathways set apart normal aging from neurodegenerative disorders. In particular, the neuronal metabolism of catecholaminergic neurotransmitters appears to be a specifically sensitive pathway that is affected in different neurodegenerations. In humans, catecholaminergic neurons are characterized by an age-related accumulation of neuromelanin (NM), rendering the soma of the neurons black. This intracellular NM appears to serve as a very efficient quencher for toxic molecules. However, when a neuron degenerates, NM is released together with its load (many undegraded cellular components, transition metals, lipids, antibiotics) contributing to initiate and worsen an eventual immune response, exacerbating the oxidative stress, ultimately leading to the neurodegenerative process. This review focuses on the analysis of the role of NM in normal aging and catecholaminergic metabolism due to its capability as a pro-oxidant and other harmful molecules, versus its involvement in oxidative stress and aberrant immune response, which it is highly dependent on NM saturation state and its extracellular release.

scholarly journals NEURONAL-SPECIFIC PROTEASOME AUGMENTATION VIA EXTENDS LIFESPAN AND REDUCES AGE-RELATED NEURODEGENERATION

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S96-S97
Author(s):  
Andrew M Pickering
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Nervous System ◽  
Drosophila Melanogaster ◽  
Stress Resistance ◽  
Brain Aging ◽  
Animal Kingdom ◽  
Age Related ◽  
And Function

Abstract Cognitive function declines with age throughout the animal kingdom and increasing evidence shows that disruption of the proteasome system contributes to this decline. The proteasome has important roles in multiple aspects of the nervous system, including synapse function and plasticity, as well as preventing cell death and senescence. We report that augmentation of proteasome function, using overexpression of the proteasome β5 subunit, enhances proteasome assembly and function. Significantly, we go on to show neuronal-specific proteasome augmentation slows age-related declines in measures of learning, memory, and circadian rhythmicity. Surprisingly neuronal specific proteasome augmentation of proteasome function also produces a robust increase of lifespan in Drosophila melanogaster. Our findings appear specific to the nervous system; ubiquitous proteasome overexpression increases oxidative stress resistance but does not impact lifespan and is detrimental to some healthspan measures. These findings demonstrate a key role of the proteasome system in brain aging.

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