scholarly journals Protein Solubility and Protein Homeostasis: A Generic View of Protein Misfolding Disorders

2011 ◽  
Vol 3 (12) ◽  
pp. a010454-a010454 ◽  
Author(s):  
M. Vendruscolo ◽  
T. P. J. Knowles ◽  
C. M. Dobson
Keyword(s):  
Protein Misfolding ◽  
Protein Solubility ◽  
Protein Homeostasis

scholarly journals Roles of Cannabidiol in Reversing Proteinopathies

2020 ◽  
Author(s):  
Raju Dash ◽  
Md. Chayan Ali ◽  
Israt Jahan ◽  
Yeasmin Akter Munni ◽  
Sarmistha Mitra ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurological Disorders ◽  
Protein Misfolding ◽  
Cannabis Sativa ◽  
Protein Homeostasis ◽  
Compelling Evidence ◽  
The Past ◽  
Clearing System ◽  
Central Nervous Systems ◽  
Preclinical And Clinical Studies

Cannabidiol is a well-known non-psychotropic phytocannabinoid from Cannabis sativa, which exerts a broad range of neuropharmacological activities in the central nervous systems. Over the past years, compelling evidence from preclinical and clinical studies support therapeutic potentials of cannabidiol in various neurological disorders, including neurodegenerative diseases. Neurodegenerative diseases are characterized by the accumulation of misfolded or aggregated protein due to the defective protein homeostasis or proteostasis network, termed as proteinopathies. Because of its role in the protein homeostasis network, cannabidiol could be a potent molecule to revert not only age-associated neurodegeneration but also other protein misfolding disorders. In this review, we discuss the potentiality of cannabidiol as a pharmacological modulator of the proteostasis network, highlighting its neuroprotective and aggregates clearing system inducing potentials in the neurodegenerative diseases.

scholarly journals Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

2015 ◽  
Vol 37 (4) ◽  
pp. 335-347 ◽  
Author(s):  
Amma F. Agyemang ◽  
Stephanie R. Harrison ◽  
Richard M. Siegel ◽  
Michael F. McDermott
Keyword(s):  
Protein Misfolding ◽  
Autoinflammatory Diseases ◽  
Protein Homeostasis

scholarly journals Proteostasis Disturbances and Inflammation in Neurodegenerative Diseases

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2183
Author(s):  
Tuuli-Maria Sonninen ◽  
Gundars Goldsteins ◽  
Nihay Laham-Karam ◽  
Jari Koistinaho ◽  
Šárka Lehtonen
Keyword(s):  
Neurodegenerative Diseases ◽  
Protein Misfolding ◽  
Inflammatory Responses ◽  
Biological Response ◽  
Protein Damage ◽  
Protein Homeostasis ◽  
Cellular Functions ◽  
Regenerative Capacity ◽  
Age Related ◽  
Lateral Sclerosis

Protein homeostasis (proteostasis) disturbances and inflammation are evident in normal aging and some age-related neurodegenerative diseases. While the proteostasis network maintains the integrity of intracellular and extracellular functional proteins, inflammation is a biological response to harmful stimuli. Cellular stress conditions can cause protein damage, thus exacerbating protein misfolding and leading to an eventual overload of the degradation system. The regulation of proteostasis network is particularly important in postmitotic neurons due to their limited regenerative capacity. Therefore, maintaining balanced protein synthesis, handling unfolding, refolding, and degrading misfolded proteins are essential to preserve all cellular functions in the central nervous sysytem. Failing proteostasis may trigger inflammatory responses in glial cells, and the consequent release of inflammatory mediators may lead to disturbances in proteostasis. Here, we review the mechanisms of proteostasis and inflammatory response, emphasizing their role in the pathological hallmarks of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Furthermore, we discuss the interplay between proteostatic stress and excessive immune response that activates inflammation and leads to dysfunctional proteostasis.

scholarly journals A Screen to Identify Cellular Modulators of Soluble Levels of an Amyotrophic Lateral Sclerosis (ALS)–Causing Mutant SOD1

2011 ◽  
Vol 16 (9) ◽  
pp. 974-985 ◽  
Author(s):  
Balajee R. Somalinga ◽  
Gregory A. Miller ◽  
Hiba T. Malik ◽  
W. Christian Wigley ◽  
Philip J. Thomas
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
High Throughput Screening ◽  
Protein Misfolding ◽  
Mammalian Cells ◽  
Protein Solubility ◽  
Global Scale ◽  
Cdna Clones ◽  
Mutant Sod1 ◽  
Cellular Targets ◽  
Lateral Sclerosis

The molecular pathology of many protein misfolding, toxic gain-of-function diseases, such as amyotrophic lateral sclerosis (ALS), is not well understood. Although protein misfolding and aggregation are common themes in these diseases, efforts to identify cellular factors that regulate this process in an unbiased fashion and on a global scale have been lacking. Using an adapted version of an extant β-gal-based protein solubility assay, an expression screen for cellular modulators of solubility of an ALS-causing mutant SOD1 was carried out in mammalian cells. Following fluorescence-activated cell sorting enrichment of a mouse spinal cord cDNA library for gene products that increased SOD1 solubility, high-throughput screening of the cDNA pools from this enriched fraction was employed to identify pools containing relevant modulators. Positive pools, containing approximately 10 cDNA clones each, were diluted and rescreened iteratively until individual clones that improved SOD1 folding/solubility were identified. Genes with profound effects in the solubility assay were selected for validation by independent biochemical assays. Six of 10 validated genes had a significant effect on SOD1 solubility and folding in a SOD1 promoter-driven β-gal assay, indicating that global screening of cellular targets using such protein solubility/folding assay is viable and can be adapted for other misfolding diseases.

scholarly journals Roles of the nucleotide exchange factor and chaperone Hsp110 in cellular proteostasis and diseases of protein misfolding

2018 ◽  
Vol 399 (10) ◽  
pp. 1215-1221 ◽  
Author(s):  
Unekwu M. Yakubu ◽  
Kevin A. Morano
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Molecular Chaperones ◽  
Protein Misfolding ◽  
Recent Progress ◽  
Cellular Protein ◽  
Protein Homeostasis ◽  
Nucleotide Exchange ◽  
Exchange Factor ◽  
Nucleotide Exchange Factor

Abstract Cellular protein homeostasis (proteostasis) is maintained by a broad network of proteins involved in synthesis, folding, triage, repair and degradation. Chief among these are molecular chaperones and their cofactors that act as powerful protein remodelers. The growing realization that many human pathologies are fundamentally diseases of protein misfolding (proteopathies) has generated interest in understanding how the proteostasis network impacts onset and progression of these diseases. In this minireview, we highlight recent progress in understanding the enigmatic Hsp110 class of heat shock protein that acts as both a potent nucleotide exchange factor to regulate activity of the foldase Hsp70, and as a passive chaperone capable of recognizing and binding cellular substrates on its own, and its integration into the proteostasis network.

scholarly journals The Cys Sense: Thiol Redox Switches Mediate Life Cycles of Cellular Proteins

Biomolecules ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 469
Author(s):  
Meytal Radzinski ◽  
Tal Oppenheim ◽  
Norman Metanis ◽  
Dana Reichmann
Keyword(s):  
Protein Misfolding ◽  
Redox Regulation ◽  
Cell Damage ◽  
Life Cycles ◽  
Future Research ◽  
Protein Homeostasis ◽  
Thiol Redox ◽  
The Individual ◽  
Growth And Aging ◽  
Cysteine Thiols

Protein homeostasis is an essential component of proper cellular function; however, sustaining protein health is a challenging task, especially during the aerobic lifestyle. Natural cellular oxidants may be involved in cell signaling and antibacterial defense; however, imbalanced levels can lead to protein misfolding, cell damage, and death. This merges together the processes of protein homeostasis and redox regulation. At the heart of this process are redox-regulated proteins or thiol-based switches, which carefully mediate various steps of protein homeostasis across folding, localization, quality control, and degradation pathways. In this review, we discuss the “redox code” of the proteostasis network, which shapes protein health during cell growth and aging. We describe the sources and types of thiol modifications and elaborate on diverse strategies of evolving antioxidant proteins in proteostasis networks during oxidative stress conditions. We also highlight the involvement of cysteines in protein degradation across varying levels, showcasing the importance of cysteine thiols in proteostasis at large. The individual examples and mechanisms raised open the door for extensive future research exploring the interplay between the redox and protein homeostasis systems. Understanding this interplay will enable us to re-write the redox code of cells and use it for biotechnological and therapeutic purposes.

scholarly journals Bacterial Protein Homeostasis Disruption as a Therapeutic Intervention

2021 ◽  
Vol 8 ◽  
Author(s):  
Laleh Khodaparast ◽  
Guiqin Wu ◽  
Ladan Khodaparast ◽  
Béla Z. Schmidt ◽  
Frederic Rousseau ◽  
...  
Keyword(s):  
Cell Viability ◽  
Protein Misfolding ◽  
Bacterial Infections ◽  
Multidrug Resistant ◽  
Protein Homeostasis ◽  
Bacterial Cells ◽  
Hydrophobic Core ◽  
Turnover Rates ◽  
Root Cause ◽  
Protein Misfolding And Aggregation

Cells have evolved a complex molecular network, collectively called the protein homeostasis (proteostasis) network, to produce and maintain proteins in the appropriate conformation, concentration and subcellular localization. Loss of proteostasis leads to a reduction in cell viability, which occurs to some degree during healthy ageing, but is also the root cause of a group of diverse human pathologies. The accumulation of proteins in aberrant conformations and their aggregation into specific beta-rich assemblies are particularly detrimental to cell viability and challenging to the protein homeostasis network. This is especially true for bacteria; it can be argued that the need to adapt to their changing environments and their high protein turnover rates render bacteria particularly vulnerable to the disruption of protein homeostasis in general, as well as protein misfolding and aggregation. Targeting bacterial proteostasis could therefore be an attractive strategy for the development of novel antibacterial therapeutics. This review highlights advances with an antibacterial strategy that is based on deliberately inducing aggregation of target proteins in bacterial cells aiming to induce a lethal collapse of protein homeostasis. The approach exploits the intrinsic aggregation propensity of regions residing in the hydrophobic core regions of the polypeptide sequence of proteins, which are genetically conserved because of their essential role in protein folding and stability. Moreover, the molecules were designed to target multiple proteins, to slow down the build-up of resistance. Although more research is required, results thus far allow the hope that this strategy may one day contribute to the arsenal to combat multidrug-resistant bacterial infections.

scholarly journals Regulation of Age-Related Protein Toxicity

2021 ◽  
Vol 9 ◽  
Author(s):  
Anita Pras ◽  
Ellen A. A. Nollen
Keyword(s):  
Protein Misfolding ◽  
Model Organisms ◽  
Amyloid Formation ◽  
Protein Homeostasis ◽  
Control Mechanisms ◽  
Toxic Protein ◽  
The Past ◽  
Age Related ◽  
Protein Misfolding And Aggregation ◽  
Protein Toxicity

Proteome damage plays a major role in aging and age-related neurodegenerative diseases. Under healthy conditions, molecular quality control mechanisms prevent toxic protein misfolding and aggregation. These mechanisms include molecular chaperones for protein folding, spatial compartmentalization for sequestration, and degradation pathways for the removal of harmful proteins. These mechanisms decline with age, resulting in the accumulation of aggregation-prone proteins that are harmful to cells. In the past decades, a variety of fast- and slow-aging model organisms have been used to investigate the biological mechanisms that accelerate or prevent such protein toxicity. In this review, we describe the most important mechanisms that are required for maintaining a healthy proteome. We describe how these mechanisms decline during aging and lead to toxic protein misassembly, aggregation, and amyloid formation. In addition, we discuss how optimized protein homeostasis mechanisms in long-living animals contribute to prolonging their lifespan. This knowledge might help us to develop interventions in the protein homeostasis network that delay aging and age-related pathologies.

scholarly journals Cellular proteostasis decline in human senescence

2019 ◽  
Author(s):  
Niv Sabath ◽  
Flonia Levy-Adam ◽  
Amal Younis ◽  
Kinneret Rozales ◽  
Anatoly Meller ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Nuclear Localization ◽  
Transcriptional Activation ◽  
Protein Misfolding ◽  
Cellular Aging ◽  
Protein Homeostasis ◽  
Human Aging ◽  
Transcriptional Responses ◽  
Significant Deterioration ◽  
Stress Sensing

AbstractProteostasis collapse, the diminished ability to maintain protein homeostasis, has been established as a hallmark of nematode aging. However, whether proteostasis collapse occurs in humans has remained unclear. Here we demonstrate that proteostasis decline is intrinsic to human senescence. Using transcriptome-wide characterization of gene expression, splicing and translation, we found a significant deterioration in the transcriptional activation of the heat shock response in stressed senescent cells. Furthermore, phosphorylated HSF1 nuclear localization and distribution were impaired in senescence. Interestingly, alternative splicing regulation was also dampened. Surprisingly, we found a decoupling between different Unfolded Protein Response (UPR) branches in stressed senescent cells. While young cells initiated UPR-related translational and transcriptional regulatory responses, senescent cells showed enhanced translational regulation and ER stress sensing, however they were unable to trigger UPR-related transcriptional responses. This was accompanied by diminished ATF6 nuclear localization in stressed senescent cells. Finally, we revealed a deterioration of proteasome function in senescence following heat stress, which did not recover upon return to normal temperature. Together, our data unraveled a deterioration in the ability to mount dynamic stress transcriptional programs upon human senescence with broad implications on proteostasis control, and connected proteostasis decline to human aging.SignificanceProtein homeostasis (proteostasis), the balance between protein synthesis, folding, and degradation, is thought to deteriorate with age, and the prevalence of protein misfolding diseases, e.g. Alzheimer’s, Parkinson’s etc., with human aging is increased. However, while in worms this phenomenon has been well established, in humans it remained unclear. Here we show that proteostasis is declined in human senescence, i.e. cellular aging. We found that while stress sensing is enhanced in senescent cells, and their response at the level of protein synthesis is intact, they fail to properly activate multiple programs required for stress adaptation at the level of gene transcription. Our findings support the notion that proteostasis decline may have major implications on human aging.

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