scholarly journals The Role of Protein S-Nitrosylation in Protein Misfolding-Associated Diseases

Life ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 705
Author(s):  
Yun-Jin Ju ◽  
Hye-Won Lee ◽  
Ji-Woong Choi ◽  
Min-Sik Choi
Keyword(s):  
Protein Misfolding ◽  
Nitrosative Stress ◽  
Protein S ◽  
Misfolded Proteins ◽  
No Production ◽  
Target Proteins ◽  
Ubiquitin Protein Ligase ◽  
Associated Diseases ◽  
The Relationship

Abnormal and excessive nitrosative stress contributes to neurodegenerative disease associated with the production of pathological levels of misfolded proteins. The accumulated findings strongly suggest that excessive NO production can induce and deepen these pathological processes, particularly by the S-nitrosylation of target proteins. Therefore, the relationship between S-nitrosylated proteins and the accumulation of misfolded proteins was reviewed. We particularly focused on the S-nitrosylation of E3-ubiquitin-protein ligase, parkin, and endoplasmic reticulum chaperone, PDI, which contribute to the accumulation of misfolded proteins. In addition to the target proteins being S-nitrosylated, NOS, which produces NO, and GSNOR, which inhibits S-nitrosylation, were also suggested as potential therapeutic targets for protein misfolding-associated diseases.

scholarly journals Chaperone-mediated hierarchical control in targeting misfolded proteins to aggresomes

2011 ◽  
Vol 22 (18) ◽  
pp. 3277-3288 ◽  
Author(s):  
Xingqian Zhang ◽  
Shu-Bing Qian
Keyword(s):  
Protein Folding ◽  
Protein Misfolding ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Hierarchical Control ◽  
Dominant Negative ◽  
Misfolded Proteins ◽  
Interacting Protein ◽  
Aggresome Formation

Protein misfolding is a common event in living cells. Molecular chaperones not only assist protein folding; they also facilitate the degradation of misfolded polypeptides. When the intracellular degradative capacity is exceeded, juxtanuclear aggresomes are formed to sequester misfolded proteins. Despite the well-established role of chaperones in both protein folding and degradation, how chaperones regulate the aggregation process remains controversial. Here we investigate the molecular mechanisms underlying aggresome formation in mammalian cells. Analysis of the chaperone requirements for the fate of misfolded proteins reveals an unexpected role of heat shock protein 70 (Hsp70) in promoting aggresome formation. This proaggregation function of Hsp70 relies on the interaction with the cochaperone ubiquitin ligase carboxyl terminal of Hsp70/Hsp90 interacting protein (CHIP). Disrupting Hsp70–CHIP interaction prevents the aggresome formation, whereas a dominant-negative CHIP mutant sensitizes the aggregation of misfolded protein. This accelerated aggresome formation also relies on the stress-induced cochaperone Bcl2-associated athanogene 3. Our results indicate that a hierarchy of cochaperone interaction controls different aspects of the intracellular protein triage decision, extending the function of Hsp70 from folding and degradation to aggregation.

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 Role of hydrogen sulfide and polysulfides in neurological diseases: focus on protein S-Persulfidation

2020 ◽  
Vol 18 ◽  
Author(s):  
Hai-Jian Sun ◽  
Zhi-Yuan Wu ◽  
Xiao-Wei Nie ◽  
Jin-Song Bian
Keyword(s):  
Hydrogen Sulfide ◽  
Protein Modification ◽  
Neurological Diseases ◽  
Protein S ◽  
The Body ◽  
Memory Decline ◽  
Target Proteins ◽  
Therapeutic Development ◽  
The Central Nervous System

: Hydrogen sulfide (H2S) and hydrogen polysulfides are recognized as important signaling molecules that are generated physiologically in the body, including the central nervous system (CNS). Studies have shown that these two molecules are involved in cytoprotection against oxidative stress and inflammatory response. In the brain system, H2S and polysulfides exert multiple functions in both health and diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington's disease (HD), memory decline, and glioma. Mechanistically, S-Persulfidation (also known as S-sulfuration or S-sulfhydration) of target proteins is believed to be a fundamental mechanism that underlies H2S-regulated signaling pathways. Cysteine S-Persulfidation is an important paradigm of post-translational protein modification in the process of H2S signaling. This model is established as a critical redox mechanism to regulate numerous biological functions, especially in H2S-mediated neuroprotection and neurogenesis. Although the current research of S-Persulfidation is still in its infancy, accumulative evidence suggests that protein S-Persulfidation may share similar characteristics with protein S-nitrosylation. In this review, we will provide a comprehensive insight into the S-Persulfidation biology of H2S and polysulfides in neurological ailments and presume potential avenues for therapeutic development in these disorders based on S-Persulfidation of target proteins.

Cysteine in Alzheimer's Disease

2020 ◽  
pp. 326-353
Author(s):  
Suvarna P. Ingale ◽  
Rupali Patil ◽  
Aman B. Upaganlawar
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Protein Misfolding ◽  
Nitrosative Stress ◽  
Aβ Peptide ◽  
Abnormal Protein ◽  
Structural Part ◽  
Neurodegenerative Process

Alzheimer's disease (AD) is characterized by selective loss of neurons in the hippocampus and neocortex due to abnormalities in proteins, mainly Aβ peptide and tau protein, in the form of abnormal protein aggregations or depositions in neurons. Recently oxidative/nitrosative stress has been identified as an important facilitator of neurodegeneration in AD. Cysteine-dependent proteins are known to be associated with the neurodegenerative process. Such cysteine-dependent enzyme proteins are proteases, antioxidant enzymes, kinases, phosphatases, and also non-enzymatic proteins such that utilize cysteine as a structural part of the catalytic site. This chapter deals with the role of cysteine in handling reactive oxygen/nitrogen species during oxidative/nitrosative stress and posttranslational modification of proteins causing protein misfolding or protein aggregation during neurodegeneration associated with AD.

scholarly journals The Role of S-Nitrosylation and S-Glutathionylation of Protein Disulphide Isomerase in Protein Misfolding and Neurodegeneration

2013 ◽  
Vol 2013 ◽  
pp. 1-15 ◽  
Author(s):  
M. Halloran ◽  
S. Parakh ◽  
J. D. Atkin
Keyword(s):  
Neurodegenerative Diseases ◽  
Er Stress ◽  
Protein Misfolding ◽  
Molecular Mechanisms ◽  
Nitrosative Stress ◽  
Therapeutic Interventions ◽  
Oxidative And Nitrosative Stress ◽  
Protective Function ◽  
Protein Disulphide Isomerase

Neurodegenerative diseases involve the progressive loss of neurons, and a pathological hallmark is the presence of abnormal inclusions containing misfolded proteins. Although the precise molecular mechanisms triggering neurodegeneration remain unclear, endoplasmic reticulum (ER) stress, elevated oxidative and nitrosative stress, and protein misfolding are important features in pathogenesis. Protein disulphide isomerase (PDI) is the prototype of a family of molecular chaperones and foldases upregulated during ER stress that are increasingly implicated in neurodegenerative diseases. PDI catalyzes the rearrangement and formation of disulphide bonds, thus facilitating protein folding, and in neurodegeneration may act to ameliorate the burden of protein misfolding. However, an aberrant posttranslational modification of PDI, S-nitrosylation, inhibits its protective function in these conditions. S-nitrosylation is a redox-mediated modification that regulates protein function by covalent addition of nitric oxide- (NO-) containing groups to cysteine residues. Here, we discuss the evidence for abnormal S-nitrosylation of PDI (SNO-PDI) in neurodegeneration and how this may be linked to another aberrant modification of PDI, S-glutathionylation. Understanding the role of aberrant S-nitrosylation/S-glutathionylation of PDI in the pathogenesis of neurodegenerative diseases may provide insights into novel therapeutic interventions in the future.

scholarly journals Transcriptional Response ofCandida albicansto Nitric Oxide and the Role of theYHB1Gene in Nitrosative Stress and Virulence

2005 ◽  
Vol 16 (10) ◽  
pp. 4814-4826 ◽  
Author(s):  
Bethann S. Hromatka ◽  
Suzanne M. Noble ◽  
Alexander D. Johnson
Keyword(s):  
Nitric Oxide ◽  
Nitrosative Stress ◽  
Transcriptional Response ◽  
Innate Immune ◽  
No Production ◽  
Human Fungal Pathogen ◽  
Genome Wide ◽  
Prime Determinant

Here, we investigate how Candida albicans, the most prevalent human fungal pathogen, protects itself from nitric oxide (.NO), an antimicrobial compound produced by the innate immune system. We show that exposure of C. albicans to.NO elicits a reproducible and specific transcriptional response as determined by genome-wide microarray analysis. Many genes are transiently induced or repressed by.NO, whereas a set of nine genes remain at elevated levels during.NO exposure. The most highly induced gene in this latter category is YHB1, a flavohemoglobin that detoxifies.NO in C. albicans and other microbes. We show that C. albicans strains deleted for YHB1 have two phenotypes in vitro; they are hypersensitive to.NO and they are hyperfilamentous. In a mouse model of disseminated candidiasis, a YHB1 deleted C. albicans strain shows moderately attenuated virulence, but the virulence defect is not suppressed by deletion of the host NOS2 gene. These results suggest that.NO production is not a prime determinant of virulence in the mouse tail vein model of candidiasis and that the attenuated virulence of a yhb1Δ/yhb1Δ strain is attributable to a defect other than its reduced ability to detoxify.NO.

Choosing a Markov blanket

2020 ◽  
Vol 43 ◽  
Author(s):  
Thomas Parr
Keyword(s):  
Markov Blanket ◽  
Target Article ◽  
The Relationship

Abstract This commentary focuses upon the relationship between two themes in the target article: the ways in which a Markov blanket may be defined and the role of precision and salience in mediating the interactions between what is internal and external to a system. These each rest upon the different perspectives we might take while “choosing” a Markov blanket.

Staring Down Death

Crisis ◽  
2016 ◽  
Vol 37 (3) ◽  
pp. 212-217 ◽  
Author(s):  
Thomas E. Joiner ◽  
Melanie A. Hom ◽  
Megan L. Rogers ◽  
Carol Chu ◽  
Ian H. Stanley ◽  
...  
Keyword(s):  
Suicide Risk ◽  
Clinical Utility ◽  
Blink Rate ◽  
Specific Task ◽  
Careful Planning ◽  
Eye Blink ◽  
Eye Blinks ◽  
Potential Clinical Utility ◽  
The Relationship

Abstract. Background: Lowered eye blink rate may be a clinically useful indicator of acute, imminent, and severe suicide risk. Diminished eye blink rates are often seen among individuals engaged in heightened concentration on a specific task that requires careful planning and attention. Indeed, overcoming one’s biological instinct for survival through suicide necessitates premeditation and concentration; thus, a diminished eye blink rate may signal imminent suicidality. Aims: This article aims to spur research and clinical inquiry into the role of eye blinks as an indicator of acute suicide risk. Method: Literature relevant to the potential connection between eye blink rate and suicidality was reviewed and synthesized. Results: Anecdotal, cognitive, neurological, and conceptual support for the relationship between decreased blink rate and suicide risk is outlined. Conclusion: Given that eye blinks are a highly observable behavior, the potential clinical utility of using eye blink rate as a marker of suicide risk is immense. Research is warranted to explore the association between eye blink rate and acute suicide risk.

Parenting Behaviors and Anxiety in Young Adults

2015 ◽  
Vol 36 (3) ◽  
pp. 170-176 ◽  
Author(s):  
Erin N. Stevens ◽  
Joseph R. Bardeen ◽  
Kyle W. Murdock
Keyword(s):  
Effortful Control ◽  
Parenting Behaviors ◽  
Protective Role ◽  
Anxiety Symptoms ◽  
Interactive Effects ◽  
Parental Overprotection ◽  
High Control ◽  
Development Of Anxiety ◽  
The Relationship

Parenting behaviors – specifically behaviors characterized by high control, intrusiveness, rejection, and overprotection – and effortful control have each been implicated in the development of anxiety pathology. However, little research has examined the protective role of effortful control in the relation between parenting and anxiety symptoms, specifically among adults. Thus, we sought to explore the unique and interactive effects of parenting and effortful control on anxiety among adults (N = 162). Results suggest that effortful control uniquely contributes to anxiety symptoms above and beyond that of any parenting behavior. Furthermore, effortful control acted as a moderator of the relationship between parental overprotection and anxiety, such that overprotection is associated with anxiety only in individuals with lower levels of effortful control. Implications for potential prevention and intervention efforts which specifically target effortful control are discussed. These findings underscore the importance of considering individual differences in self-regulatory abilities when examining associations between putative early-life risk factors, such as parenting, and anxiety symptoms.

Social Support, Emotional Intelligence, and Posttraumatic Stress Disorder Symptoms

2016 ◽  
Vol 37 (1) ◽  
pp. 31-39 ◽  
Author(s):  
Nicole L. Hofman ◽  
Austin M. Hahn ◽  
Christine K. Tirabassi ◽  
Raluca M. Gaher
Keyword(s):  
Social Support ◽  
Posttraumatic Stress Disorder ◽  
Emotional Intelligence ◽  
Protective Factors ◽  
Posttraumatic Stress ◽  
Stress Disorder ◽  
Traumatic Events ◽  
Ptsd Symptoms ◽  
The Relationship

Abstract. Exposure to traumatic events and the associated risk of developing Posttraumatic stress disorder (PTSD) symptoms is a significant and overlooked concern in the college population. It is important for current research to identify potential protective factors associated with the development and maintenance of PTSD symptoms unique to this population. Emotional intelligence and perceived social support are two identified protective factors that influence the association between exposure to traumatic events and PTSD symptomology. The current study examined the mediating role of social support in the relationship between emotional intelligence and PTSD symptoms. Participants included 443 trauma-exposed university students who completed online questionnaires. The results of this study indicated that social support mediates the relationship between emotional intelligence and reported PTSD symptoms. Thus, emotional intelligence is significantly associated with PTSD symptoms and social support may play an integral role in the relationship between emotional intelligence and PTSD. The current study is the first to investigate the role of social support in the relationship between emotional intelligence and PTSD symptoms. These findings have important treatment and prevention implications with regard to PTSD.

Sign in / Sign up

Export Citation Format

Share Document