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.

Glutamine repeats: structural hypotheses and neurodegeneration

2002 ◽  
Vol 30 (4) ◽  
pp. 548-551 ◽  
Author(s):  
L. Masino ◽  
A. Pastore
Keyword(s):  
Protein Misfolding ◽  
Trinucleotide Repeats ◽  
Intranuclear Inclusions ◽  
The Past ◽  
Cag Trinucleotide Repeats ◽  
Protein Misfolding And Aggregation ◽  
Polyglutamine Protein ◽  
Molecular Bases ◽  
Protein Models

A growing number of neurodegenerative diseases are caused by expansion of CAG trinucleotide repeats coding for polyglutamine. The presence of intranuclear inclusions in the affected neuronal cells has suggested a mechanism for pathogenesis based on protein misfolding and aggregation. Detailed understanding of these phenomena is therefore crucial in order to rationalize different phases of the diseases. In the past decade, a few studies have focused on the structural properties of polyglutamine and on the molecular bases of the aggregation process. Most of these studies have been performed on polyglutamine peptides and protein models. Only one report is currently available on the characterization of a full-length polyglutamine protein. The structural hypotheses resulting from these studies are reviewed here.

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 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 The cellular modifier MOAG-4/SERF drives amyloid formation through charge complementation

2020 ◽  
Author(s):  
Anita Pras ◽  
Bert Houben ◽  
Francesco A. Aprile ◽  
Renée Seinstra ◽  
Rodrigo Gallardo ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Structural Changes ◽  
Colloidal Stability ◽  
Positive Charge ◽  
Amyloid Formation ◽  
Related Protein ◽  
Age Related ◽  
Related Proteins ◽  
Protein Toxicity ◽  
Charge Interactions

AbstractWhile aggregation-prone proteins are known to accelerate ageing and cause age-related diseases, the cellular mechanisms that drive their cytotoxicity remain unresolved. The orthologous proteins MOAG-4, SERF1A and SERF2 have recently been identified as cellular modifiers of such cytotoxicity. Using a peptide array screening approach on human amyloidogenic proteins, we found that SERF2 interacted with specific patterns of negatively charged and hydrophobic, aromatic amino acids. The absence of such patterns, or the neutralization of the positive charge in SERF2, prevented these interactions and abolished the amyloid-promoting activity of SERF2. In a protein aggregation model in the nematode C. elegans, protein aggregation was suppressed by mutating the endogenous locus of MOAG-4 to neutralize charge. Our data indicate that charge interactions are required for MOAG-4 and SERF2 to promote aggregation. Such charged interactions might accelerate the primary nucleation of amyloid by initiating structural changes and by decreasing colloidal stability. Our finding that negatively charged segments are overrepresented in amyloid-forming proteins suggests that inhibition of charge interactions deserves exploration as a strategy to target age-related protein toxicity.Significance StatementHow aging causes relatively common diseases such as Alzheimer’s and Parkinson’s is still a mystery. Since toxic structural changes in proteins are likely to be responsible, we investigated biological mechanisms that could drive such changes. We made use of a modifying factor called SERF2, which accelerates structural changes and aggregation of several disease-related proteins. Through a peptide-binding screen, we found that SERF2 acts on negatively charged protein regions. The abundance of such regions in the disease-related proteins explains why SERF has its effect. Removing positive charge in SERF was sufficient to suppress protein aggregation in models for disease. We propose that blocking charge-interactions with SERF or other modifiers could serve as a general approach to treat age-related protein toxicity.

scholarly journals A comparative meta-analysis of membraneless organelle associated proteins with age related proteome of C. elegans

2021 ◽  
Author(s):  
Pritam Mukherjee ◽  
Prajnadipta Panda ◽  
Prasad Kasturi
Keyword(s):  
Protein Misfolding ◽  
Meta Analysis ◽  
Adverse Conditions ◽  
C Elegans ◽  
Age Related ◽  
Associated Proteins ◽  
Altered Metabolism ◽  
Protein Misfolding And Aggregation ◽  
Cellular Components ◽  
Liquid Condensate

Proteome imbalance can lead to protein misfolding and aggregation which is associated with pathologies. Protein aggregation can also be an active, organized process and can be exploited by cells as a survival strategy. In adverse conditions, it is beneficial to deposit the proteins in a condensate rather degrading and resynthesizing. Membrane less organelles (MLOs) are biological condensates formed through liquid liquid phase separation (LLPS), involving cellular components such as nucleic acids and proteins. LLPS is a regulated process, which when perturbed, can undergo a transition from a physiological liquid condensate to pathological solid-like protein aggregates. To understand how the MLO-associated proteins (MLO-APs) behave during aging, we performed a comparative meta analysis with age related proteome of C. elegans. We found that the MLO-APs are highly abundant throughout the lifespan. Interestingly, they are aggregating more in long-lived mutant worms compared to the age matched wildtype worms. GO term analysis revealed that the cell cycle and embryonic development are among the top enriched processes in addition to RNA metabolism RNP components. Considering antagonistic pleotropic nature of these developmental genes and post mitotic status of C. elegans, we assume that these proteins phase transit during post development. As the organism ages, these MLO-APs either mature to become more insoluble or dissolve in uncontrolled manner. However, in the long-lived daf-2 mutant worms, the MLOs may attain protective states due to enhanced proteostasis components and altered metabolism that eventually make these worms more protected.

scholarly journals Rapamycin and Rapalogs

2021 ◽  
Author(s):  
Dudley Lamming
Keyword(s):  
Side Effects ◽  
Selective Inhibition ◽  
Model Organisms ◽  
Intermittent Treatment ◽  
Negative Side ◽  
Related Disease ◽  
The Past ◽  
Mechanistic Target Of Rapamycin ◽  
Age Related ◽  
Negative Side Effects

Inhibition of mTORC1 (mechanistic Target Of Rapamycin Complex 1) signaling promotes health and longevity in diverse model organisms. Over the past decade, excitement has built over the possibility that treatment with the mTORC1 inhibitor rapamycin can be utilized to treat or prevent age-related disease in humans. However, concerns over the side effects of rapamycin on immunity and metabolism have precluded the routine use of rapamycin as a geroprotective therapy. Here, we discuss the evidence that these negative side effects of rapamycin are largely mediated by off-target inhibition of a second mTOR Complex (mTORC2). Further, we discuss how intermittent treatment with rapamycin, specific dietary regimens, and new molecules may provide routes to the safer and more selective inhibition of mTORC1. We conclude that the time is ripe for the development of therapies based on the safe and selective inhibition of mTORC1 for the treatment or prevention of diseases of aging.

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 Comparative study of protein aggregation propensity and mutation tolerance between naked mole-rat and mouse

2021 ◽  
Author(s):  
Savandara Besse ◽  
Raphaël Poujol ◽  
Julie G. Hussin
Keyword(s):  
Healthy Aging ◽  
Molecular Mechanisms ◽  
Therapeutic Interventions ◽  
Model Organisms ◽  
Protein Homeostasis ◽  
Aggregation Propensity ◽  
Age Related ◽  
Mole Rat ◽  
Significant Difference ◽  
Naked Mole Rat

The molecular mechanisms of aging and life expectancy have been studied in model organisms with short lifespans. However, long-lived species may provide insights into successful strategies of healthy aging, potentially opening the door for novel therapeutic interventions in age-related diseases. Notably, naked mole-rats, the longest-lived rodent, present attenuated aging phenotypes in comparison to mice. Their resistance toward oxidative stress has been proposed as one hallmark of their healthy aging, suggesting their ability to maintain cell homeostasis, and specifically their protein homeostasis. To identify the general principles behind their protein homeostasis robustness, we compared the aggregation propensity and mutation tolerance of naked mole-rat and mouse orthologous proteins. Our analysis showed no proteome-wide differential effects in aggregation propensity and mutation tolerance between these species, but several subsets of proteins with a significant difference in aggregation propensity. We found an enrichment of proteins with higher aggregation propensity in naked mole-rat involved the inflammasome complex, and in nucleic acid binding. On the other hand, proteins with lower aggregation propensity in naked mole-rat have a significantly higher mutation tolerance compared to the rest of the proteins. Among them, we identified proteins known to be associated with neurodegenerative and age-related diseases. These findings highlight the intriguing hypothesis about the capacity of the naked mole-rat proteome to delay aging through its proteomic intrinsic architecture.

scholarly journals The ageing lung under stress

2020 ◽  
Vol 29 (156) ◽  
pp. 200126
Author(s):  
Martina Korfei ◽  
BreAnne MacKenzie ◽  
Silke Meiners
Keyword(s):  
Oxidative Stress ◽  
Stress Responses ◽  
Respiratory Diseases ◽  
Structural Changes ◽  
The Elderly ◽  
Protein Homeostasis ◽  
Control Mechanisms ◽  
Age Related ◽  
Numerous Cell ◽  
Adaptive Stress Response

Healthy ageing of the lung involves structural changes but also numerous cell-intrinsic and cell-extrinsic alterations. Among them are the age-related decline in central cellular quality control mechanisms such as redox and protein homeostasis. In this review, we would like to provide a conceptual framework of how impaired stress responses in the ageing lung, as exemplified by dysfunctional redox and protein homeostasis, may contribute to onset and progression of COPD and idiopathic pulmonary fibrosis (IPF). We propose that age-related imbalanced redox and protein homeostasis acts, amongst others (e.g. cellular senescence), as a “first hit” that challenges the adaptive stress-response pathways of the cell, increases the level of oxidative stress and renders the lung susceptible to subsequent injury and disease. In both COPD and IPF, additional environmental insults such as smoking, air pollution and/or infections then serve as “second hits” which contribute to persistently elevated oxidative stress that overwhelms the already weakened adaptive defence and repair pathways in the elderly towards non-adaptive, irremediable stress thereby promoting development and progression of respiratory diseases. COPD and IPF are thus distinct horns of the same devil, “lung ageing”.

scholarly journals Location, location, location: subcellular protein partitioning in proteostasis and aging

2021 ◽  
Author(s):  
Anita V. Kumar ◽  
Louis R. Lapierre
Keyword(s):  
Quality Control ◽  
Protein Folding ◽  
Protein Synthesis ◽  
Cell Survival ◽  
Recent Literature ◽  
Protein Homeostasis ◽  
Control Mechanisms ◽  
Somatic Maintenance ◽  
Age Related ◽  
Protein Partitioning

AbstractSomatic maintenance and cell survival rely on proper protein homeostasis to ensure reliable functions across the cell and to prevent proteome collapse. Maintaining protein folding and solubility is central to proteostasis and is coordinated by protein synthesis, chaperoning, and degradation capacities. An emerging aspect that influences proteostasis is the dynamic protein partitioning across different subcellular structures and compartments. Here, we review recent literature related to nucleocytoplasmic partitioning of proteins, nuclear and cytoplasmic quality control mechanisms, and their impact on the development of age-related diseases. We also highlight new points of entry to modulate spatially-regulated proteostatic mechanisms to delay aging.

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