scholarly journals Proteostasis Failure in Neurodegenerative Diseases: Focus on Oxidative Stress

2020 ◽  
Vol 2020 ◽  
pp. 1-21 ◽  
Author(s):  
Annika Höhn ◽  
Antonella Tramutola ◽  
Roberta Cascella
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Diseases ◽  
Protein Misfolding ◽  
Protein Quality ◽  
Cellular Protein ◽  
Protein Levels ◽  
A Cell ◽  
Lysosomal System ◽  
Turn Over ◽  
Protein Dysfunction

Protein homeostasis or proteostasis is an essential balance of cellular protein levels mediated through an extensive network of biochemical pathways that regulate different steps of the protein quality control, from the synthesis to the degradation. All proteins in a cell continuously turn over, contributing to development, differentiation, and aging. Due to the multiple interactions and connections of proteostasis pathways, exposure to stress conditions may cause various types of protein damage, altering cellular homeostasis and disrupting the entire network with additional cellular stress. Furthermore, protein misfolding and/or alterations during protein synthesis results in inactive or toxic proteins, which may overload the degradation mechanisms. The maintenance of a balanced proteome, preventing the formation of impaired proteins, is accomplished by two major catabolic routes: the ubiquitin proteasomal system (UPS) and the autophagy-lysosomal system. The proteostasis network is particularly important in nondividing, long-lived cells, such as neurons, as its failure is implicated with the development of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. These neurological disorders share common risk factors such as aging, oxidative stress, environmental stress, and protein dysfunction, all of which alter cellular proteostasis, suggesting that general mechanisms controlling proteostasis may underlay the etiology of these diseases. In this review, we describe the major pathways of cellular proteostasis and discuss how their disruption contributes to the onset and progression of neurodegenerative diseases, focusing on the role of oxidative stress.

scholarly journals Oxidative stress-induced parkin misfolding, aggregation, and toxicity

2020 ◽  
Author(s):  
Martin Duennwald ◽  
Gary S. Shaw ◽  
Mohammad A. Esmaeili ◽  
Jane R. Rylett ◽  
Susanne Schmid ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Disulfide Bonds ◽  
Protein Misfolding ◽  
Protein Quality ◽  
Normal Growth ◽  
Growth Conditions ◽  
Cellular Protein ◽  
Loss Of Function ◽  
Underlying Mechanisms

Abstract Background: Excess oxidative stress and protein misfolding are major hallmarks of neurodegenerative disease, including Parkinson’s disease (PD). Mutations in the genes encoding the ubiquitin ligase parkin cause autosomal recessive juvenile forms of Parkinsonism by the loss of parkin function in mitochondrial homeostasis and cellular protein quality control, generally. Dysfunction of parkin might also contribute to sporadic forms of PD, yet the underlying mechanisms remain mostly unexplored. Methods: We obtained key results from studies in human PD brains, a mouse model, yeast, cultured neuronal cells, and in vitro biochemistry. Human postmortem Medial Temporal Gyrus tissue was fixed for immunohistochemistry. We performed biochemical analyses of protein lysates from human brain, mouse brain, yeast and cells to assess parkin modification by oxidative stress under normal growth conditions and more so under oxidative stress. Results: Our results reveal that oxidative stress damages parkin by inducing the formation of aberrant intra- and inter-molecular disulfide bonds, leading to parkin misfolding and inclusion formation, which is toxic to cells. We furthermore find that parkin is most severely oxidized in its active conformation. Conclusion: Collectively, our study identifies a mechanism by which protein oxidation can contribute to neurodegeneration in PD by combining loss of function with toxic gain of function mechanisms.

Evidence Linking Protein Misfolding to Quality Control in Progressive Neurodegenerative Diseases

2020 ◽  
Vol 20 (23) ◽  
pp. 2025-2043 ◽  
Author(s):  
Md. Tanvir Kabir ◽  
Md. Sahab Uddin ◽  
Ahmed Abdeen ◽  
Ghulam Md Ashraf ◽  
Asma Perveen ◽  
...  
Keyword(s):  
Quality Control ◽  
Neurodegenerative Diseases ◽  
Protein Misfolding ◽  
Mammalian Cells ◽  
Protein Quality ◽  
Prion Diseases ◽  
Cellular Protein ◽  
Sequence Motif ◽  
Native Proteins ◽  
Usual Process

Several proteolytic systems including ubiquitin (Ub)-proteasome system (UPS), chaperonemediated autophagy (CMA), and macroautophagy are used by the mammalian cells to remove misfolded proteins (MPs). UPS mediates degradation of most of the MPs, where Ub-conjugated substrates are deubiquitinated, unfolded, and passed through the proteasome’s narrow chamber, and eventually break into smaller peptides. It has been observed that the substrates that show a specific degradation signal, the KFERQ sequence motif, can be delivered to and go through CMA-mediated degradation in lysosomes. Macroautophagy can help in the degradation of substrates that are prone to aggregation and resistant to both the CMA and UPS. In the aforesaid case, cargoes are separated into autophagosomes before lysosomal hydrolase-mediated degradation. Even though the majority of the aggregated and MPs in the human proteome can be removed via cellular protein quality control (PQC), some mutant and native proteins tend to aggregate into β-sheet-rich oligomers that exhibit resistance to all identified proteolytic processes and can, therefore, grow into extracellular plaques or inclusion bodies. Indeed, the buildup of protease-resistant aggregated and MPs is a usual process underlying various protein misfolding disorders, including neurodegenerative diseases (NDs) for example Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and prion diseases. In this article, we have focused on the contribution of PQC in the degradation of pathogenic proteins in NDs.

scholarly journals Mycobacterium tuberculosis Rv0991c Is a Redox-Regulated Molecular Chaperone

mBio ◽  
2020 ◽  
Vol 11 (4) ◽  
Author(s):  
Samuel H. Becker ◽  
Kathrin Ulrich ◽  
Avantika Dhabaria ◽  
Beatrix Ueberheide ◽  
William Beavers ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Quality Control ◽  
Mycobacterium Tuberculosis ◽  
Molecular Chaperone ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Cellular Protein ◽  
Content Type ◽  
Hsp70 Chaperone

ABSTRACT The bacterial pathogen Mycobacterium tuberculosis is the leading cause of death by an infectious disease among humans. Here, we describe a previously uncharacterized M. tuberculosis protein, Rv0991c, as a molecular chaperone that is activated by oxidation. Rv0991c has homologs in most bacterial lineages and appears to function analogously to the well-characterized Escherichia coli redox-regulated chaperone Hsp33, despite a dissimilar protein sequence. Rv0991c is transcriptionally coregulated with hsp60 and hsp70 chaperone genes in M. tuberculosis, suggesting that Rv0991c functions with these chaperones in maintaining protein quality control. Supporting this hypothesis, we found that, like oxidized Hsp33, oxidized Rv0991c prevents the aggregation of a model unfolded protein in vitro and promotes its refolding by the M. tuberculosis Hsp70 chaperone system. Furthermore, Rv0991c interacts with DnaK and can associate with many other M. tuberculosis proteins. We therefore propose that Rv0991c, which we named “Ruc” (redox-regulated protein with unstructured C terminus), represents a founding member of a new chaperone family that protects M. tuberculosis and other species from proteotoxicity during oxidative stress. IMPORTANCE M. tuberculosis infections are responsible for more than 1 million deaths per year. Developing effective strategies to combat this disease requires a greater understanding of M. tuberculosis biology. As in all cells, protein quality control is essential for the viability of M. tuberculosis, which likely faces proteotoxic stress within a host. Here, we identify an M. tuberculosis protein, Ruc, that gains chaperone activity upon oxidation. Ruc represents a previously unrecognized family of redox-regulated chaperones found throughout the bacterial superkingdom. Additionally, we found that oxidized Ruc promotes the protein-folding activity of the essential M. tuberculosis Hsp70 chaperone system. This work contributes to a growing body of evidence that oxidative stress provides a particular strain on cellular protein stability.

scholarly journals A cell-based platform for oxidative stress monitoring in motor neurons using genetically encoded biosensors of H2O2

2021 ◽  
Author(s):  
Elizaveta I. Ustyantseva ◽  
Suren M. Zakian ◽  
Sergey P. Medvedev
Keyword(s):  
Oxidative Stress ◽  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Diseases ◽  
Motor Neurons ◽  
Model Systems ◽  
Patient Specific ◽  
Ipsc Line ◽  
Stress Monitoring ◽  
A Cell ◽  
Lateral Sclerosis

ABSTRACTBackgroundOxidative stress plays an important role in the development of neurodegenerative diseases: it either can be the initiator or part of a pathological cascade leading to the neuron’s death. Although a lot of methods are known for oxidative stress study, most of them operate on non-native cellular substrates or interfere with the cell functioning. Genetically encoded (GE) biosensors of oxidative stress demonstrated their general functionality and overall safety in various live systems. However, there is still insufficient data regarding their use for research of disease-related phenotypes in relevant model systems, such as human cells.MethodsWe applied CRISPR/Cas9 genome editing to introduce mutations (c.272A>C and c.382G>C) in the associated with amyotrophic lateral sclerosis SOD1 gene of induced pluripotent stem cells (iPSC) obtained from a healthy individual. Using CRISPR/Cas9, we modified these mutant iPSC lines, as well as the parental iPSC line, and a patient-specific SOD1D91A/D91A iPSC line with ratiometric GE biosensors of cytoplasmic (Cyto-roGFP2-Orp1) and mitochondrial (Mito-roGFP2-Orp1) H2O2. The biosensors sequences along with a specific transactivator for doxycycline-controllable expression were inserted in the “safe harbor” AAVS1 (adeno-associated virus site 1) locus. We differentiated these transgenic iPSCs into motor neurons and investigated the functionality of the biosensors in such a system. We measured relative oxidation in the cultured motor neurons and its dependence on culture conditions, age, and genotype, as well as kinetics of H2O2 elimination in real-time.ResultsWe developed a cell-based platform consisting of isogenic iPSC lines with different genotypes associated with amyotrophic lateral sclerosis. The iPSC lines were modified with GE biosensors of cytoplasmic and mitochondrial H2O2. We provide proof-of-principle data showing that this approach may be suitable for monitoring oxidative stress in cell models of various neurodegenerative diseases as the biosensors reflect the redox state of neurons.ConclusionWe found that the GE biosensors inserted in the AAVS1 locus remain functional in motor neurons and reflect pathological features of mutant motor neurons, although the readout largely depends on the severity of the mutation.

scholarly journals Possibilities of Combinatorial Therapy: Insulin Dysregulation and the Growth Hormone Perspective on Neurodegeneration

2021 ◽  
Author(s):  
Priyanka Sengupta ◽  
Debashis Mukhopadhyay
Keyword(s):  
Oxidative Stress ◽  
Growth Hormone ◽  
Neurodegenerative Diseases ◽  
Insulin Receptor ◽  
Neurodegenerative Disorders ◽  
Protein Misfolding ◽  
Combinatorial Therapy ◽  
Insulin Pathway ◽  
Insulin Dysregulation ◽  
Receptor Family

RTKs have been reported to be implicated in several neurodegenerative disorders and the roles of insulin receptor family have emerged as a key common pathway across diseases. Thus we focussed on the Insulin receptor family and discussed the irregulation from the growth hormone axis. The signaling, regulation and physiology of the production in liver and CNS has never been discussed in signaling perspectives and is extremely crucial for understanding the possibilities of IGF1 in neurodegeneration specifically. The commonalities across neurodegenerative diseases such as oxidative stress, mitochondrial dysfunction, and protein misfolding and insulin pathway anomalies have been elucidated and correlated with the insulin pathway. The crosstalk possibilities of the pathways, along with other regulatory modes for the development of combinatorial therapy have been discussed to visualize a common platform for neurodegenerative diseases including AD, PD, HD, ALS and FTD. Furthermore, the incretin based therapies that have gradually emerged as alternatives for insulin based therapy due to its inherent drawback of resistance has been briefly discussed.

Neurodegenerative Diseases as Protein Misfolding Disorders

2016 ◽  
Author(s):  
Tomohiro Nakamura ◽  
Stuart A. Lipton
Keyword(s):  
Quality Control ◽  
Neurodegenerative Diseases ◽  
Protein Misfolding ◽  
Protein Quality ◽  
Protein S ◽  
Ubiquitin Proteasome System ◽  
Misfolded Proteins ◽  
Redox Stress ◽  
Chemical Mechanisms ◽  
Ubiquitin Proteasome

Neurodegenerative diseases (NDDs) often represent disorders of protein folding. Rather than large aggregates, recent evidence suggests that soluble oligomers of misfolded proteins are the most neurotoxic species. Emerging evidence points to small, soluble oligomers of misfolded proteins as the cause of synaptic dysfunction and loss, the major pathological correlate to disease progression in many NDDs including Alzheimer’s disease. The protein quality control machinery of the cell, which includes molecular chaperones as found in the endoplasmic reticulum (ER), the ubiquitin-proteasome system (UPS), and various forms of autophagy, can counterbalance the accumulation of misfolded proteins to some extent. Their ability to eliminate the neurotoxic effects of misfolded proteins, however, declines with age. A plausible explanation for the age-dependent deterioration of the quality control machinery involves compromise of these systems by excessive generation of reactive oxygen species (ROS), such as superoxide anion (O2-), and reactive nitrogen species (RNS), such as nitric oxide (NO). The resulting redox stress contributes to the accumulation of misfolded proteins. Here, we focus on aberrantly increased generation of NO-related species since this process appears to accelerate the manifestation of key neuropathological features, including protein misfolding. We review the chemical mechanisms of posttranslational modification by RNS such as protein S-nitrosylation of critical cysteine thiol groups and nitration of tyrosine residues, showing how they contribute to the pathogenesis of NDDs.

scholarly journals Current Trends in Neurodegeneration: Cross Talks between Oxidative Stress, Cell Death, and Inflammation

2021 ◽  
Vol 22 (14) ◽  
pp. 7432
Author(s):  
Tapan Behl ◽  
Rashita Makkar ◽  
Aayush Sehgal ◽  
Sukhbir Singh ◽  
Neelam Sharma ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Nervous System ◽  
Neurodegenerative Diseases ◽  
Neurological Diseases ◽  
Organ Systems ◽  
Ability To Regenerate ◽  
The Central Nervous System ◽  
Neuronal Degradation ◽  
Turn Over

The human body is highly complex and comprises a variety of living cells and extracellular material, which forms tissues, organs, and organ systems. Human cells tend to turn over readily to maintain homeostasis in tissues. However, postmitotic nerve cells exceptionally have an ability to regenerate and be sustained for the entire life of an individual, to safeguard the physiological functioning of the central nervous system. For efficient functioning of the CNS, neuronal death is essential, but extreme loss of neurons diminishes the functioning of the nervous system and leads to the onset of neurodegenerative diseases. Neurodegenerative diseases range from acute to chronic severe life-altering conditions like Parkinson’s disease and Alzheimer’s disease. Millions of individuals worldwide are suffering from neurodegenerative disorders with little or negligible treatment available, thereby leading to a decline in their quality of life. Neuropathological studies have identified a series of factors that explain the etiology of neuronal degradation and its progression in neurodegenerative disease. The onset of neurological diseases depends on a combination of factors that causes a disruption of neurons, such as environmental, biological, physiological, and genetic factors. The current review highlights some of the major pathological factors responsible for neuronal degradation, such as oxidative stress, cell death, and neuroinflammation. All these factors have been described in detail to enhance the understanding of their mechanisms and target them for disease management.

scholarly journals Eukaryotic Elongation Factor 3 Protects Saccharomyces cerevisiae Yeast from Oxidative Stress

Genes ◽  
2020 ◽  
Vol 11 (12) ◽  
pp. 1432
Author(s):  
Karolina Gościńska ◽  
Somayeh Shahmoradi Ghahe ◽  
Sara Domogała ◽  
Ulrike Topf
Keyword(s):  
Oxidative Stress ◽  
Protein Synthesis ◽  
Elongation Factor ◽  
Cellular Protein ◽  
Stress Conditions ◽  
Translation Elongation ◽  
Protein Levels ◽  
Eukaryotic Elongation Factor ◽  
Elongation Factor 3 ◽  
Elongation Process

Translation is a core process of cellular protein homeostasis and, thus, needs to be tightly regulated. The production of newly synthesized proteins adapts to the current needs of the cell, including the response to conditions of oxidative stress. Overall protein synthesis decreases upon oxidative stress. However, the selective production of proteins is initiated to help neutralize stress conditions. In contrast to higher eukaryotes, fungi require three translation elongation factors, eEF1, eEF2, and eEF3, for protein synthesis. eEF1 and eEF2 are evolutionarily conserved, but they alone are insufficient for the translation elongation process. eEF3 is encoded by two paralogous genes, YEF3 and HEF3. However, only YEF3 is essential in yeast, whereas the function of HEF3 remains unknown. To elucidate the cellular function of Hef3p, we used cells that were depleted of HEF3 and treated with H2O2 and analyzed the growth of yeast, global protein production, and protein levels. We found that HEF3 is necessary to withstand oxidative stress conditions, suggesting that Hef3p is involved in the selective production of proteins that are necessary for defense against reactive oxygen species.

scholarly journals Western Faculty Profile: Dr. Martin L. Duennwald

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Soojie Hong
Keyword(s):  
Quality Control ◽  
Amyotrophic Lateral Sclerosis ◽  
Protein Misfolding ◽  
Protein Quality ◽  
Assistant Professor ◽  
Cellular Protein ◽  
Independent Research ◽  
Biomedical Research Institute ◽  
Control Protein ◽  
Lateral Sclerosis

Dr. Martin L. Duennwald is a researcher and assistant professor at Western University. After conducting independent research at the Boston Biomedical Research Institute, he came to Western University in 2012 where he started the Duennwald Lab. His lab focuses on cellular protein quality control, protein misfolding and their pathological consequences in neurodegenerative diseases such as Huntington’s disease, Parkinson’s disease, and Amyotrophic Lateral Sclerosis (ALS).

scholarly journals Reactive Oxygen Species in Neurodegenerative Diseases: Implications in Pathogenesis and Treatment Strategies

2021 ◽  
Author(s):  
Johnson Olaleye Oladele ◽  
Adenike T. Oladiji ◽  
Oluwaseun Titilope Oladele ◽  
Oyedotun M. Oyeleke
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Neurodegenerative Diseases ◽  
Neurodegenerative Disorders ◽  
Protein Misfolding ◽  
Critical Role ◽  
Treatment Strategies ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
The Brain

Neurodegenerative diseases are debilitating disorders which compromise motor or cognitive functions and are rapidly becoming a global communal disorder with over 46.8 million people suffering dementia worldwide. Aetiological studies have showed that people who are exposed to agricultural, occupational and environmental toxic chemicals that can interfere and degenerate dopaminergic neurons are prone to developing neurodegenerative diseases such as Parkinson Disease. The complex pathogenesis of the neurodegenerative diseases remains largely unknown; however, mounting evidence suggests that oxidative stress, neuroinflammation, protein misfolding, and apoptosis are the hallmarks of the diseases. Reactive oxygen species (ROS) are chemically reactive molecules that have been implicated in the pathogenesis of neurodegenerative diseases. ROS play a critical role as high levels of oxidative stress are commonly observed in the brain of patients with neurodegenerative disorders. This chapter focus on the sources of ROS in the brain, its involvement in the pathogenesis of neurodegenerative diseases and possible ways to mitigate its damaging effects in the affected brain.

Sign in / Sign up

Export Citation Format

Share Document