Amyloid Beta

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

Advances in Medical Diagnosis, Treatment, and Care - Handbook of Research on Critical Examinations of Neurodegenerative Disorders ◽

10.4018/978-1-5225-5282-6.ch011 ◽

2019 ◽

pp. 235-251

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

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The ubiquitin–proteasome system and skeletal muscle wasting

Essays in Biochemistry ◽

10.1042/bse0410173 ◽

2005 ◽

Vol 41 ◽

pp. 173-186 ◽

Cited By ~ 110

Author(s):

Didier Attaix ◽

Sophie Ventadour ◽

Audrey Codran ◽

Daniel Béchet ◽

Daniel Taillandier ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Wasting ◽

Proteolytic Enzymes ◽

Cathepsin L ◽

Ubiquitin Proteasome System ◽

Complete Breakdown ◽

Skeletal Muscle Proteins ◽

Ubiquitin Proteasome ◽

Tripeptidyl Peptidase Ii ◽

F Box Protein

The ubiquitin–proteasome system (UPS) is believed to degrade the major contractile skeletal muscle proteins and plays a major role in muscle wasting. Different and multiple events in the ubiquitination, deubiquitination and proteolytic machineries are responsible for the activation of the system and subsequent muscle wasting. However, other proteolytic enzymes act upstream (possibly m-calpain, cathepsin L, and/or caspase 3) and downstream (tripeptidyl-peptidase II and aminopeptidases) of the UPS, for the complete breakdown of the myofibrillar proteins into free amino acids. Recent studies have identified a few critical proteins that seem necessary for muscle wasting {i.e. the MAFbx (muscle atrophy F-box protein, also called atrogin-1) and MuRF-1 [muscle-specific RING (really interesting new gene) finger 1] ubiquitin–protein ligases}. The characterization of their signalling pathways is leading to new pharmacological approaches that can be useful to block or partially prevent muscle wasting in human patients.

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A Yeast-Based Functional Assay to Study Plant N-Degron – N-Recognin Interactions

Frontiers in Plant Science ◽

10.3389/fpls.2021.806129 ◽

2022 ◽

Vol 12 ◽

Author(s):

Aida Kozlic ◽

Nikola Winter ◽

Theresia Telser ◽

Jakob Reimann ◽

Katrin Rose ◽

...

Keyword(s):

Ubiquitin Proteasome System ◽

Functional Assay ◽

The Novel ◽

In Planta ◽

Amino Terminal ◽

Weak Binding ◽

Ubiquitin Conjugating Enzyme ◽

Ubiquitin Proteasome ◽

The Stability

The N-degron pathway is a branch of the ubiquitin-proteasome system where amino-terminal residues serve as degradation signals. In a synthetic biology approach, we expressed ubiquitin ligase PRT6 and ubiquitin conjugating enzyme 2 (AtUBC2) from Arabidopsis thaliana in a Saccharomyces cerevisiae strain with mutation in its endogenous N-degron pathway. The two enzymes re-constitute part of the plant N-degron pathway and were probed by monitoring the stability of co-expressed GFP-linked plant proteins starting with Arginine N-degrons. The novel assay allows for straightforward analysis, whereas in vitro interaction assays often do not allow detection of the weak binding of N-degron recognizing ubiquitin ligases to their substrates, and in planta testing is usually complex and time-consuming.

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Pueraria lobata and Daidzein Reduce Cytotoxicity by Enhancing Ubiquitin-Proteasome System Function in SCA3-iPSC-Derived Neurons

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/8130481 ◽

2019 ◽

Vol 2019 ◽

pp. 1-18

Author(s):

I-Cheng Chen ◽

Kuo-Hsuan Chang ◽

Yi-Jing Chen ◽

Yi-Chun Chen ◽

Guey-Jen Lee-Chen ◽

...

Keyword(s):

Proteasome Inhibitor ◽

Caspase 3 ◽

Neurodegenerative Disorder ◽

Ubiquitin Proteasome System ◽

Proteasome Activity ◽

Cag Repeats ◽

Spinocerebellar Ataxia Type ◽

Pueraria Lobata ◽

Protein Ubiquitination ◽

Ubiquitin Proteasome

Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion within the ATXN3/MJD1 gene. The expanded CAG repeats encode a polyglutamine (polyQ) tract at the C-terminus of the ATXN3 protein. ATXN3 containing expanded polyQ forms aggregates, leading to subsequent cellular dysfunctions including an impaired ubiquitin-proteasome system (UPS). To investigate the pathogenesis of SCA3 and develop potential therapeutic strategies, we established induced pluripotent stem cell (iPSC) lines from SCA3 patients (SCA3-iPSC). Neurons derived from SCA3-iPSCs formed aggregates that are positive to the polyQ marker 1C2. Treatment with the proteasome inhibitor, MG132, on SCA3-iPSC-derived neurons downregulated proteasome activity, increased production of radical oxygen species (ROS), and upregulated the cleaved caspase 3 level and caspase 3 activity. This increased susceptibility to the proteasome inhibitor can be rescued by a Chinese herbal medicine (CHM) extract NH037 (from Pueraria lobata) and its constituent daidzein via upregulating proteasome activity and reducing protein ubiquitination, oxidative stress, cleaved caspase 3 level, and caspase 3 activity. Our results successfully recapitulate the key phenotypes of the neurons derived from SCA3 patients, as well as indicate the potential of NH037 and daidzein in the treatment for SCA3 patients.

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

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2021.733012 ◽

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.

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Exercise Training-Increased FBXO32 and FOXO1 in a Gender-Dependent Manner in Mild Cognitively Impaired African Americans: GEMS-1 Study

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.641758 ◽

2021 ◽

Vol 13 ◽

Author(s):

Fikru B. Bedada ◽

Oyonumo E. Ntekim ◽

Evaristus O. Nwulia ◽

Thomas V. Fungwe ◽

Sheeba Raaj Nadarajah ◽

...

Keyword(s):

African Americans ◽

Gene Expression Analysis ◽

Ubiquitin Proteasome System ◽

Cognitively Impaired ◽

Dependent Manner ◽

Specific Exercise ◽

Ubiquitin Proteasome ◽

The Brain ◽

Gender Specific

The ubiquitin proteasome system (UPS) and FOXOs transcription factors play a pivotal role in cellular clearance and minimizing the accumulation of Aβ in neurodegeneration (ND). In African Americans (AAs) with mild cognitive impairment (MCI), the role of components of UPS and FOXOs; and whether they are amenable to exercise effects is unknown. We hypothesized that exercise can enhance cellular clearance systems during aging and ND by increasing expressions of FBXO32 and FOXO1. To test this hypothesis, we used TaqMan gene expression analysis in peripheral blood (PB) to investigate the component of UPS and FOXOs; and provide mechanistic insight at baseline, during exercise, and in both genders. At baseline, levels of FBXO32 were higher in women than in men. In our attempt to discern gender-specific exercise-related changes, we observed that levels of FBXO32 increased in men but not in women. Similarly, levels of FOXO1 increased in men only. These data suggest that a graded dose of FBXO32 and FOXO1 may be beneficial when PB cells carrying FBXO32 and FOXO1 summon into the brain in response to Alzheimer’s disease (AD) perturbation (docking station PB cells). Our observation is consistent with emerging studies that exercise allows the trafficking of blood factors. Given the significance of FBXO32 and FOXO1 to ND and associated muscle integrity, our findings may explain, at least in part, the benefits of exercise on memory, associated gait, and balance perturbation acknowledged to herald the emergence of MCI.

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Degradation of Tyrosine Hydroxylase by the Ubiquitin-Proteasome System in the Pathogenesis of Parkinson’s Disease and Dopa-Responsive Dystonia

International Journal of Molecular Sciences ◽

10.3390/ijms21113779 ◽

2020 ◽

Vol 21 (11) ◽

pp. 3779 ◽

Cited By ~ 1

Author(s):

Ichiro Kawahata ◽

Kohji Fukunaga

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Tyrosine Hydroxylase ◽

Ubiquitin Proteasome System ◽

Degradation Pathway ◽

The Novel ◽

Gene Encoding ◽

Dopaminergic Systems ◽

Dopamine Biosynthesis ◽

Ubiquitin Proteasome

Nigrostriatal dopaminergic systems govern physiological functions related to locomotion, and their dysfunction leads to movement disorders, such as Parkinson’s disease and dopa-responsive dystonia (Segawa disease). Previous studies revealed that expression of the gene encoding nigrostriatal tyrosine hydroxylase (TH), a rate-limiting enzyme of dopamine biosynthesis, is reduced in Parkinson’s disease and dopa-responsive dystonia; however, the mechanism of TH depletion in these disorders remains unclear. In this article, we review the molecular mechanism underlying the neurodegeneration process in dopamine-containing neurons and focus on the novel degradation pathway of TH through the ubiquitin-proteasome system to advance our understanding of the etiology of Parkinson’s disease and dopa-responsive dystonia. We also introduce the relation of α-synuclein propagation with the loss of TH protein in Parkinson’s disease as well as anticipate therapeutic targets and early diagnosis of these diseases.

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Abstract 991: The Novel BTB/POZ Protein, RhoBTB3, Regulates Mitochondrial Function Via The Ubiquitin Proteasome System

Circulation ◽

10.1161/circ.116.suppl_16.ii_196-d ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Shinsuke Yuasa ◽

Takeshi Onizuka ◽

Shimoji Kenichiro ◽

Yohei Ohno ◽

Masaharu Katayama ◽

...

Keyword(s):

Heart Failure ◽

Ubiquitin Proteasome System ◽

Adult Brain ◽

Protein Synthesis Inhibitor ◽

List Type ◽

The Novel ◽

Rat Cardiomyocytes ◽

Adult Heart ◽

Btb Domain ◽

Ubiquitin Proteasome

Although BTB/POZ family proteins play a critical role in the development of various organs, and are recently known as a substrate adaptor of CUL3 ubiquitin ligases, the involvement of these proteins in heart development remains unknown. We recently isolated the novel protein, RhoBTB3, an 83-kD protein which comprises an N-terminal Rho GTPase resembling domain and two tandem BTB domains. The purpose of this study was to investigate the molecular and functional characteristics of this protein in mice heart. [Methods and Results] RhoBTB3 was faintly expressed in the embryonic heart, but was strongly expressed in the adult heart. It was weakly expressed in adult brain and testis. RhoBTB3-GFP fusion protein cDNA was transfected into primary cultured rat cardiomyocytes using adenovirus. Fluorescence microscopy revealed that RhoBTB3 was located at the cytoplasm of living cardiomyocytes. HA-tagged RhoBTB3 and MYC-tagged CUL family proteins (1 – 5) were co-transfected into COS7 cells. RhoBTB3 was co-immunoprecipitated with CUL3 in vitro , but not with other CUL proteins. The various mutant RhoBTB3 and wild type CUL3 protein were examined by immunoprecipitation assay. Both the first BTB domain and second BTB domain can bind to CUL3 protein independently. It was difficult to detect RhoBTB3 in protein analysis. To determine whether or not RhoBTB3 itself could be the Cul3 ubiquitin target, RhoBTB3 protein was measured under the presence of proteasome inhibitor MG132 and protein synthesis inhibitor cycloheximide. The RhoBTB3 protein was immediately degraded and dropped below the detection level within 2 hours. The transgenic mice which overexpressed the heart-restricted RhoBTB3 were healthy at a young age. But after 3 months, they gradually showed heart failure and finally fell into sudden death. Interestingly before heart failure, electron microscopy demonstrated that mitochondria dramatically increased in number and showed deformity in RhoBTB3 transgenic hearts. [Conclusions] RhoBTB3 is mainly expressed in the adult heart, and its protein was rapidly degraded with the CUL3-mediated ubiquitin proteasome system in the heart. The overexpression of RhoBTB3 caused a marked increase in abnormal mitochondria, followed by severe heart failure.

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Intramitochondrial proteostasis is directly coupled to α-synuclein and amyloid β1-42 pathologies

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.011650 ◽

2020 ◽

Vol 295 (30) ◽

pp. 10138-10152 ◽

Cited By ~ 3

Author(s):

Janin Lautenschläger ◽

Sara Wagner-Valladolid ◽

Amberley D. Stephens ◽

Ana Fernández-Villegas ◽

Colin Hockings ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Protein Import ◽

Protein Quality ◽

Neurodegenerative Disorder ◽

Mitochondrial Protein ◽

Amyloid Β ◽

Ubiquitin Proteasome System ◽

Protein Homeostasis ◽

Mitochondrial Inhibitors ◽

Ubiquitin Proteasome

Mitochondrial dysfunction has long been implicated in the neurodegenerative disorder Parkinson's disease (PD); however, it is unclear how mitochondrial impairment and α-synuclein pathology are coupled. Using specific mitochondrial inhibitors, EM analysis, and biochemical assays, we report here that intramitochondrial protein homeostasis plays a major role in α-synuclein aggregation. We found that interference with intramitochondrial proteases, such as HtrA2 and Lon protease, and mitochondrial protein import significantly aggravates α-synuclein seeding. In contrast, direct inhibition of mitochondrial complex I, an increase in intracellular calcium concentration, or formation of reactive oxygen species, all of which have been associated with mitochondrial stress, did not affect α-synuclein pathology. We further demonstrate that similar mechanisms are involved in amyloid-β 1-42 (Aβ42) aggregation. Our results suggest that, in addition to other protein quality control pathways, such as the ubiquitin–proteasome system, mitochondria per se can influence protein homeostasis of cytosolic aggregation-prone proteins. We propose that approaches that seek to maintain mitochondrial fitness, rather than target downstream mitochondrial dysfunction, may aid in the search for therapeutic strategies to manage PD and related neuropathologies.

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