Ubiquitin–Proteasome System Impairment and MPTP-Induced Oxidative Stress in the Brain of C57BL/6 Wild-type and GSTP Knockout Mice

Alzheimer's disease (AD), exhibiting accumulation of amyloid beta (Aβ) peptide as a foremost protagonist, is one of the top five causes of deaths. It is a neurodegenerative disorder (ND) that causes a progressive decline in memory and cognitive abilities. It is characterized by deposition of Aβ plaques and neurofibrillary tangles (NFTs) in the neurons, which in turn causes a decline in the brain acetylcholine levels. Aβ hypothesis is the most accepted hypothesis pertaining to the pathogenesis of AD. Amyloid Precursor Protein (APP) is constitutively present in brain and it is cleaved by three proteolytic enzymes (i.e., alpha, beta, and gamma secretases). Beta and gamma secretases cleave APP to form Aβ. Ubiquitin Proteasome System (UPS) is involved in the clearing of Aβ plaques. AD also involves impairment in UPS. The novel disease-modifying approaches involve inhibition of beta and gamma secretases. A number of clinical trials are going on worldwide with moieties targeting beta and gamma secretases. This chapter deals with an overview of APP and its enzymatic cleavage leading to AD.

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Amyloid Beta

Research Anthology on Diagnosing and Treating Neurocognitive Disorders ◽

10.4018/978-1-7998-3441-0.ch001 ◽

2021 ◽

pp. 1-17

Author(s):

Abhinav Anand ◽

Neha Sharma ◽

Monica Gulati ◽

Navneet Khurana

Keyword(s):

Amyloid Beta ◽

Cognitive Abilities ◽

Neurodegenerative Disorder ◽

Proteolytic Enzymes ◽

Ubiquitin Proteasome System ◽

The Novel ◽

Ubiquitin Proteasome ◽

Causes Of Deaths ◽

Brain Acetylcholine ◽

The Brain

Alzheimer's disease (AD), exhibiting accumulation of amyloid beta (Aβ) peptide as a foremost protagonist, is one of the top five causes of deaths. It is a neurodegenerative disorder (ND) that causes a progressive decline in memory and cognitive abilities. It is characterized by deposition of Aβ plaques and neurofibrillary tangles (NFTs) in the neurons, which in turn causes a decline in the brain acetylcholine levels. Aβ hypothesis is the most accepted hypothesis pertaining to the pathogenesis of AD. Amyloid Precursor Protein (APP) is constitutively present in brain and it is cleaved by three proteolytic enzymes (i.e., alpha, beta, and gamma secretases). Beta and gamma secretases cleave APP to form Aβ. Ubiquitin Proteasome System (UPS) is involved in the clearing of Aβ plaques. AD also involves impairment in UPS. The novel disease-modifying approaches involve inhibition of beta and gamma secretases. A number of clinical trials are going on worldwide with moieties targeting beta and gamma secretases. This chapter deals with an overview of APP and its enzymatic cleavage leading to AD.

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Effects of ubiquitin C-terminal hydrolase L1 deficiency on mouse ova

Reproduction ◽

10.1530/rep-11-0128 ◽

2012 ◽

Vol 143 (3) ◽

pp. 271-279 ◽

Cited By ~ 8

Author(s):

Sayaka Koyanagi ◽

Hiroko Hamasaki ◽

Satoshi Sekiguchi ◽

Kenshiro Hara ◽

Yoshiyuki Ishii ◽

...

Keyword(s):

Electron Microscopy ◽

Transmission Electron Microscopy ◽

Endoplasmic Reticulum ◽

Proteomic Analysis ◽

Ubiquitin Proteasome System ◽

Underlying Mechanism ◽

Wild Type ◽

Transmission Electron ◽

Ubiquitin Proteasome

Maternal proteins are rapidly degraded by the ubiquitin–proteasome system during oocyte maturation in mice. Ubiquitin C-terminal hydrolase L1 (UCHL1) is highly and specifically expressed in mouse ova and is involved in the polyspermy block. However, the role of UCHL1 in the underlying mechanism of polyspermy block is poorly understood. To address this issue, we performed a comprehensive proteomic analysis to identify maternal proteins that were relevant to the role of UCHL1 in mouse ova using UCHL1-deficientgad. Furthermore, we assessed morphological features ingadmouse ova using transmission electron microscopy. NACHT, LRR, and PYD domain-containing (NALP) family proteins and endoplasmic reticulum (ER) chaperones were identified by proteomic analysis. We also found that the ‘maternal antigen that embryos require’ (NLRP5 (MATER)) protein level increased significantly ingadmouse ova compared with that in wild-type mice. In an ultrastructural study,gadmouse ova contained less ER in the cortex than in wild-type mice. These results provide new insights into the role of UCHL1 in the mechanism of polyspermy block in mouse ova.

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Lack of mitochondrial ferritin aggravated neurological deficits via enhancing oxidative stress in a traumatic brain injury murine model

Bioscience Reports ◽

10.1042/bsr20170942 ◽

2017 ◽

Vol 37 (6) ◽

Cited By ~ 9

Author(s):

Ligang Wang ◽

Libo Wang ◽

Zhibo Dai ◽

Pei Wu ◽

Huaizhang Shi ◽

...

Keyword(s):

Oxidative Stress ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Knockout Mice ◽

Brain Injuries ◽

Brain Infarction ◽

Neurological Deficits ◽

Important Correlation ◽

The Brain ◽

And Oxidative Stress

Oxidative stress has been strongly implicated in the pathogenesis of traumatic brain injury (TBI). Mitochondrial ferritin (Ftmt) is reported to be closely related to oxidative stress. However, whether Ftmt is involved in TBI-induced oxidative stress and neurological deficits remains unknown. In the present study, the controlled cortical impact model was established in wild-type and Ftmt knockout mice as a TBI model. The Ftmt expression, oxidative stress, neurological deficits, and brain injury were measured. We found that Ftmt expression was gradually decreased from 3 to 14 days post-TBI, while oxidative stress was gradually increased, as evidenced by reduced GSH and superoxide dismutase levels and elevated malondialdehyde and nitric oxide levels. Interestingly, the extent of reduced Ftmt expression in the brain was linearly correlated with oxidative stress. Knockout of Ftmt significantly exacerbated TBI-induced oxidative stress, intracerebral hemorrhage, brain infarction, edema, neurological severity score, memory impairment, and neurological deficits. However, all these effects in Ftmt knockout mice were markedly mitigated by pharmacological inhibition of oxidative stress using an antioxidant, N-acetylcysteine. Taken together, these results reveal an important correlation between Ftmt and oxidative stress after TBI. Ftmt deficiency aggravates TBI-induced brain injuries and neurological deficits, which at least partially through increasing oxidative stress levels. Our data suggest that Ftmt may be a promising molecular target for the treatment of TBI.

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Inhibition of the Ubiquitin-Proteasome System Protects Endothelial Cells from Oxidative Stress

10.1240/sav_gbm_2006_m_001490 ◽

2006 ◽

Vol 2006 (Spring) ◽

Author(s):

Silke Meiners ◽

Andrea Weller ◽

Antje Ludwig ◽

Karl Stangl ◽

Verena Stangl

Keyword(s):

Oxidative Stress ◽

Endothelial Cells ◽

Ubiquitin Proteasome System ◽

Ubiquitin Proteasome

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The Slow Wallerian Degeneration Protein, WldS, Binds Directly to VCP/p97 and Partially Redistributes It within the Nucleus

Molecular Biology of the Cell ◽

10.1091/mbc.e05-04-0375 ◽

2006 ◽

Vol 17 (3) ◽

pp. 1075-1084 ◽

Cited By ~ 41

Author(s):

Heike Laser ◽

Laura Conforti ◽

Giacomo Morreale ◽

Till G.M. Mack ◽

Molly Heyer ◽

...

Keyword(s):

Amino Acids ◽

Wallerian Degeneration ◽

Nuclear Protein ◽

Ubiquitin Proteasome System ◽

Wild Type ◽

Ubiquitin Proteasome ◽

Direct Binding ◽

Synthesis Activity ◽

Additional Role

Slow Wallerian degeneration (WldS) mutant mice express a chimeric nuclear protein that protects sick or injured axons from degeneration. The C-terminal region, derived from NAD+ synthesizing enzyme Nmnat1, is reported to confer neuroprotection in vitro. However, an additional role for the N-terminal 70 amino acids (N70), derived from multiubiquitination factor Ube4b, has not been excluded. In wild-type Ube4b, N70 is part of a sequence essential for ubiquitination activity but its role is not understood. We report direct binding of N70 to valosin-containing protein (VCP; p97/Cdc48), a protein with diverse cellular roles including a pivotal role in the ubiquitin proteasome system. Interaction with WldS targets VCP to discrete intranuclear foci where ubiquitin epitopes can also accumulate. WldS lacking its N-terminal 16 amino acids (N16) neither binds nor redistributes VCP, but continues to accumulate in intranuclear foci, targeting its intrinsic NAD+ synthesis activity to these same foci. Wild-type Ube4b also requires N16 to bind VCP, despite a more C-terminal binding site in invertebrate orthologues. We conclude that N-terminal sequences of WldS protein influence the intranuclear location of both ubiquitin proteasome and NAD+ synthesis machinery and that an evolutionary recent sequence mediates binding of mammalian Ube4b to VCP.

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Aerobic exercise training improves oxidative stress and ubiquitin proteasome system activity in heart of spontaneously hypertensive rats

Molecular and Cellular Biochemistry ◽

10.1007/s11010-015-2326-1 ◽

2015 ◽

Vol 402 (1-2) ◽

pp. 193-202 ◽

Cited By ~ 12

Author(s):

Luiz Henrique Soares de Andrade ◽

Wilson Max Almeida Monteiro de Moraes ◽

Eduardo Hiroshi Matsuo Junior ◽

Elizabeth de Orleans Carvalho de Moura ◽

Hanna Karen Moreira Antunes ◽

...

Keyword(s):

Oxidative Stress ◽

Exercise Training ◽

Aerobic Exercise ◽

Spontaneously Hypertensive Rats ◽

Ubiquitin Proteasome System ◽

Aerobic Exercise Training ◽

Hypertensive Rats ◽

Spontaneously Hypertensive ◽

System Activity ◽

Ubiquitin Proteasome

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Innate immunity to yeast prions: Btn2p and Cur1p curing of the [URE3] prion is prevented by 60S ribosomal protein deficiency or ubiquitin/proteasome system overactivity

Genetics ◽

10.1093/genetics/iyab013 ◽

2021 ◽

Author(s):

Evgeny E Bezsonov ◽

Herman K Edskes ◽

Reed B Wickner

Keyword(s):

Ubiquitin Ligase ◽

Ribosomal Subunit ◽

Ubiquitin Proteasome System ◽

Negative Regulator ◽

Large Ribosomal Subunit ◽

Seed Number ◽

Wild Type ◽

Yeast Prions ◽

In The Wild ◽

Ubiquitin Proteasome

Abstract [URE3] is an amyloid-based prion of Ure2p, a negative regulator of poor nitrogen source catabolism in Saccharomyces cerevisiae. Overproduced Btn2p or its paralog Cur1p, in processes requiring Hsp42, cure the [URE3] prion. Btn2p cures by collecting Ure2p amyloid filaments at one place in the cell. We find that rpl4aΔ, rpl21aΔ, rpl21bΔ, rpl11bΔ and rpl16bΔ (large ribosomal subunit proteins) or ubr2Δ (ubiquitin ligase targeting Rpn4p, an activator of proteasome genes) reduce curing by overproduced Btn2p or Cur1p. Impaired curing in ubr2Δ or rpl21bΔ is restored by an rpn4Δ mutation. No effect of rps14aΔ or rps30bΔ on curing was observed, indicating that 60S subunit deficiency specifically impairs curing. Levels of Hsp42p, Sis1p or Btn3p are unchanged in rpl4aΔ, rpl21bΔ or ubr2Δ mutants. Overproduction of Cur1p or Btn2p was enhanced in rpn4Δ and hsp42Δ mutants, lower in ubr2Δ strains, and restored to above wild type levels in rpn4Δ ubr2Δ strains. As in the wild-type, Ure2N-GFP colocalizes with Btn2-RFP in rpl4aΔ, rpl21bΔ or ubr2Δ strains, but not in hsp42Δ. Btn2p/Cur1p overproduction cures [URE3] variants with low seed number, but seed number is not increased in rpl4aΔ, rpl21bΔ or ubr2Δ mutants. Knockouts of genes required for the protein sorting function of Btn2p did not affect curing of [URE3], nor did inactivation of the Hsp104 prion-curing activity. Overactivity of the ubiquitin/proteasome system, resulting from 60S subunit deficiency or ubr2Δ, may impair Cur1p and Btn2p curing of [URE3] by degrading Cur1p, Btn2p or another component of these curing systems.

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

10.21203/rs.3.rs-595308/v1 ◽

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.

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