scholarly journals Ubiquitin and Parkinson's disease through the looking glass of genetics

2017 ◽  
Vol 474 (9) ◽  
pp. 1439-1451 ◽  
Author(s):  
Helen Walden ◽  
Miratul M.K. Muqit
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Quality Control ◽  
Protein Misfolding ◽  
Protein Quality ◽  
Neuronal Loss ◽  
Protein Quality Control ◽  
Biochemical Alterations ◽  
Ubiquitin System ◽  
Novel Therapeutic Strategies

Biochemical alterations found in the brains of Parkinson's disease (PD) patients indicate that cellular stress is a major driver of dopaminergic neuronal loss. Oxidative stress, mitochondrial dysfunction, and ER stress lead to impairment of the homeostatic regulation of protein quality control pathways with a consequent increase in protein misfolding and aggregation and failure of the protein degradation machinery. Ubiquitin signalling plays a central role in protein quality control; however, prior to genetic advances, the detailed mechanisms of how impairment in the ubiquitin system was linked to PD remained mysterious. The discovery of mutations in the α-synuclein gene, which encodes the main protein misfolded in PD aggregates, together with mutations in genes encoding ubiquitin regulatory molecules, including PTEN-induced kinase 1 (PINK1), Parkin, and FBX07, has provided an opportunity to dissect out the molecular basis of ubiquitin signalling disruption in PD, and this knowledge will be critical for developing novel therapeutic strategies in PD that target the ubiquitin system.

scholarly journals Crosstalk between Endoplasmic Reticulum Stress and Protein Misfolding in Neurodegenerative Diseases

2013 ◽  
Vol 2013 ◽  
pp. 1-22 ◽  
Author(s):  
Cláudia M. F. Pereira
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Neurodegenerative Diseases ◽  
Protein Misfolding ◽  
Secretory Pathway ◽  
Protein Quality ◽  
Prion Diseases ◽  
Protein Quality Control ◽  
Subcellular Compartment ◽  
Novel Therapeutic Strategies

Under physiological conditions, the endoplasmic reticulum (ER) is a central subcellular compartment for protein quality control in the secretory pathway that prevents protein misfolding and aggregation. Instrumental in protein quality control in the ER is the unfolded protein response (UPR), which is activated upon ER stress to reestablish homeostasis through a sophisticated transcriptionally and translationally regulated signaling network. However, this response can lead to apoptosis if the stress cannot be alleviated. The presence of abnormal protein aggregates containing specific misfolded proteins is recognized as the basis of numerous human conformational disorders, including neurodegenerative diseases. Here, I will highlight the overwhelming evidence that the presence of specific aberrant proteins in Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), prion diseases, and Amyotrophic Lateral Sclerosis (ALS) is intimately associated with perturbations in the ER protein quality control machinery that become incompetent to restore protein homeostasis and shift adaptive programs toward the induction of apoptotic signaling to eliminate irreversibly damaged neurons. Increasing our understanding about the deadly crosstalk between ER dysfunction and protein misfolding in these neurodegenerative diseases may stimulate the development of novel therapeutic strategies able to support neuronal survival and ameliorate disease progression.

Protein Quality Control Degradation in the Nucleus

2018 ◽  
Vol 87 (1) ◽  
pp. 725-749 ◽  
Author(s):  
Charisma Enam ◽  
Yifat Geffen ◽  
Tommer Ravid ◽  
Richard G. Gardner
Keyword(s):  
Quality Control ◽  
Protein Misfolding ◽  
Protein Quality ◽  
Current Knowledge ◽  
Protein Quality Control ◽  
Ubiquitin Proteasome System ◽  
Misfolded Proteins ◽  
Cellular Processes ◽  
Human Disorders ◽  
Protein Misfolding And Aggregation

Nuclear proteins participate in diverse cellular processes, many of which are essential for cell survival and viability. To maintain optimal nuclear physiology, the cell employs the ubiquitin-proteasome system to eliminate damaged and misfolded proteins in the nucleus that could otherwise harm the cell. In this review, we highlight the current knowledge about the major ubiquitin-protein ligases involved in protein quality control degradation (PQCD) in the nucleus and how they orchestrate their functions to eliminate misfolded proteins in different nuclear subcompartments. Many human disorders are causally linked to protein misfolding in the nucleus, hence we discuss major concepts that still need to be clarified to better understand the basis of the nuclear misfolded proteins’ toxic effects. Additionally, we touch upon potential strategies for manipulating nuclear PQCD pathways to ameliorate diseases associated with protein misfolding and aggregation in the nucleus.

scholarly journals Modulating protein quality control

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Lars Plate ◽  
Ryan J Paxman ◽  
R Luke Wiseman ◽  
Jeffery W Kelly
Keyword(s):  
Quality Control ◽  
Small Molecules ◽  
Unfolded Protein Response ◽  
Protein Misfolding ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Misfolding Diseases ◽  
Protein Response

Small molecules that modulate the unfolded protein response have the potential to treat a variety of human protein misfolding diseases.

scholarly journals Protein quality control degron-containing substrates are differentially targeted in the cytoplasm and nucleus by ubiquitin ligases

Genetics ◽  
2020 ◽  
Vol 217 (1) ◽  
Author(s):  
Christopher M Hickey ◽  
Carolyn Breckel ◽  
Mengwen Zhang ◽  
William C Theune ◽  
Mark Hochstrasser
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Ubiquitin Ligases ◽  
Ubiquitin Proteasome System ◽  
Human Cells ◽  
Covalent Attachment ◽  
Protein Levels ◽  
Ubiquitin System ◽  
C Terminus

Abstract Intracellular proteolysis by the ubiquitin–proteasome system regulates numerous processes and contributes to protein quality control (PQC) in all eukaryotes. Covalent attachment of ubiquitin to other proteins is specified by the many ubiquitin ligases (E3s) expressed in cells. Here we determine the E3s in Saccharomyces cerevisiae that function in degradation of proteins bearing various PQC degradation signals (degrons). The E3 Ubr1 can function redundantly with several E3s, including nuclear-localized San1, endoplasmic reticulum/nuclear membrane-embedded Doa10, and chromatin-associated Slx5/Slx8. Notably, multiple degrons are targeted by more ubiquitylation pathways if directed to the nucleus. Degrons initially assigned as exclusive substrates of Doa10 were targeted by Doa10, San1, and Ubr1 when directed to the nucleus. By contrast, very short hydrophobic degrons—typical targets of San1—are shown here to be targeted by Ubr1 and/or San1, but not Doa10. Thus, distinct types of PQC substrates are differentially recognized by the ubiquitin system in a compartment-specific manner. In human cells, a representative short hydrophobic degron appended to the C-terminus of GFP-reduced protein levels compared with GFP alone, consistent with a recent study that found numerous natural hydrophobic C-termini of human proteins can act as degrons. We also report results of bioinformatic analyses of potential human C-terminal degrons, which reveal that most peptide substrates of Cullin-RING ligases (CRLs) are of low hydrophobicity, consistent with previous data showing CRLs target degrons with specific sequences. These studies expand our understanding of PQC in yeast and human cells, including the distinct but overlapping PQC E3 substrate specificity of the cytoplasm and nucleus.

scholarly journals The σ R regulon of Streptomyces coelicolor A3(2) reveals a key role in protein quality control during disulphide stress

Microbiology ◽  
2010 ◽  
Vol 156 (6) ◽  
pp. 1661-1672 ◽  
Author(s):  
Dimitris Kallifidas ◽  
Derek Thomas ◽  
Phillip Doughty ◽  
Mark S. B. Paget
Keyword(s):  
Quality Control ◽  
Sigma Factor ◽  
Protein Misfolding ◽  
Protein Quality ◽  
Streptomyces Coelicolor ◽  
Protein Quality Control ◽  
Redox Balance ◽  
Regulatory Pathways ◽  
Thioredoxin System ◽  
Cellular Thiol

Diamide is an artificial disulphide-generating electrophile that mimics an oxidative shift in the cellular thiol–disulphide redox state (disulphide stress). The Gram-positive bacterium Streptomyces coelicolor senses and responds to disulphide stress through the σ R–RsrA system, which comprises an extracytoplasmic function (ECF) sigma factor and a redox-active anti-sigma factor. Known targets that aid in the protection and recovery from disulphide stress include the thioredoxin system and genes involved in producing the major thiol buffer mycothiol. Here we determine the global response to diamide in wild-type and sigR mutant backgrounds to understand the role of σ R in this response and to reveal additional regulatory pathways that allow cells to cope with disulphide stress. In addition to thiol oxidation, diamide was found to cause protein misfolding and aggregation, which elicited the induction of the HspR heat-shock regulon. Although this response is σ R-independent, σ R does directly control Clp and Lon ATP-dependent AAA(+) proteases, which may partly explain the reduced ability of a sigR mutant to resolubilize protein aggregates. σ R also controls msrA and msrB methionine sulphoxide reductase genes, implying that σ R–RsrA is responsible for the maintenance of both cysteine and methionine residues during oxidative stress. This work shows that the σ R–RsrA system plays a more significant role in protein quality control than previously realized, and emphasizes the importance of controlling the cellular thiol–disulphide redox balance.

scholarly journals USP7 regulates ALS-associated proteotoxicity and quality control through the NEDD4L–SMAD pathway

2020 ◽  
Vol 117 (45) ◽  
pp. 28114-28125
Author(s):  
Tao Zhang ◽  
Goran Periz ◽  
Yu-Ning Lu ◽  
Jiou Wang
Keyword(s):  
Quality Control ◽  
Neurodegenerative Diseases ◽  
Protein Misfolding ◽  
Mammalian Cells ◽  
Transforming Growth Factor ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Transforming Growth Factor Β ◽  
Misfolded Proteins ◽  
A Genome

An imbalance in cellular homeostasis occurring as a result of protein misfolding and aggregation contributes to the pathogeneses of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Here, we report the identification of a ubiquitin-specific protease, USP7, as a regulatory switch in a protein quality-control system that defends against proteotoxicity. A genome-wide screen in aCaenorhabditis elegansmodel of SOD1-linked ALS identified the USP7 ortholog as a suppressor of proteotoxicity in the nervous system. The actions of USP7 orthologs on misfolded proteins were found to be conserved inDrosophilaand mammalian cells. USP7 acts on protein quality control through the SMAD2 transcription modulator of the transforming growth factor β pathway, which activates autophagy and enhances the clearance of misfolded proteins. USP7 deubiquitinates the E3 ubiquitin ligase NEDD4L, which mediates the degradation of SMAD2. Inhibition of USP7 protected against proteotoxicity in mammalian neurons, and SMAD2 was found to be dysregulated in the nervous systems of ALS patients. These findings reveal a regulatory pathway of protein quality control that is implicated in the proteotoxicity-associated neurodegenerative diseases.

scholarly journals Nuclear Ubiquitin-Proteasome Pathways in Proteostasis Maintenance

Biomolecules ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 54
Author(s):  
Dina Franić ◽  
Klara Zubčić ◽  
Mirta Boban
Keyword(s):  
Quality Control ◽  
Protein Misfolding ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Ubiquitin Proteasome System ◽  
Cytoplasmic Proteins ◽  
Ubiquitin Proteasome ◽  
A Cell ◽  
Protein Misfolding And Aggregation ◽  
Order Complexes

Protein homeostasis, or proteostasis, is crucial for the functioning of a cell, as proteins that are mislocalized, present in excessive amounts, or aberrant due to misfolding or other type of damage can be harmful. Proteostasis includes attaining the correct protein structure, localization, and the formation of higher order complexes, and well as the appropriate protein concentrations. Consequences of proteostasis imbalance are evident in a range of neurodegenerative diseases characterized by protein misfolding and aggregation, such as Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis. To protect the cell from the accumulation of aberrant proteins, a network of protein quality control (PQC) pathways identifies the substrates and direct them towards refolding or elimination via regulated protein degradation. The main pathway for degradation of misfolded proteins is the ubiquitin-proteasome system. PQC pathways have been first described in the cytoplasm and the endoplasmic reticulum, however, accumulating evidence indicates that the nucleus is an important PQC compartment for ubiquitination and proteasomal degradation of not only nuclear, but also cytoplasmic proteins. In this review, we summarize the nuclear ubiquitin-proteasome pathways involved in proteostasis maintenance in yeast, focusing on inner nuclear membrane-associated degradation (INMAD) and San1-mediated protein quality control.

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