Protein homeostasis in models of aging and age-related conformational disease (original) (raw)

Extensive accumulation of misfolded protein aggregates during natural aging and senescence

Frontiers in Aging Neuroscience

Accumulation of misfolded protein aggregates is a hallmark event in many age-related protein misfolding disorders, including some of the most prevalent and insidious neurodegenerative diseases. Misfolded protein aggregates produce progressive cell damage, organ dysfunction, and clinical changes, which are common also in natural aging. Thus, we hypothesized that aging is associated to the widespread and progressive misfolding and aggregation of many proteins in various tissues. In this study, we analyzed whether proteins misfold, aggregate, and accumulate during normal aging in three different biological systems, namely senescent cells, Caenorhabditis elegans, and mouse tissues collected at different times from youth to old age. Our results show a significant accumulation of misfolded protein aggregates in aged samples as compared to young materials. Indeed, aged samples have between 1.3 and 2.5-fold (depending on the biological system) higher amount of insoluble proteins than young ...

Role of Protein Misfolding and Proteostasis Deficiency in Protein Misfolding Diseases and Aging

International Journal of Cell Biology, 2013

The misfolding, aggregation, and tissue accumulation of proteins are common events in diverse chronic diseases, known as protein misfolding disorders. Many of these diseases are associated with aging, but the mechanism for this connection is unknown. Recent evidence has shown that the formation and accumulation of protein aggregates may be a process frequently occurring during normal aging, but it is unknown whether protein misfolding is a cause or a consequence of aging. To combat the formation of these misfolded aggregates cells have developed complex and complementary pathways aiming to maintain protein homeostasis. These protective pathways include the unfolded protein response, the ubiquitin proteasome system, autophagy, and the encapsulation of damaged proteins in aggresomes. In this paper we review the current knowledge on the role of protein misfolding in disease and aging as well as the implication of deficiencies in the proteostasis cellular pathways in these processes. It is likely that further understanding of the mechanisms involved in protein misfolding and the natural defense pathways may lead to novel strategies for treatment of age-dependent protein misfolding disorders and perhaps aging itself.

Protein aggregation as a paradigm of aging

Biochimica et Biophysica Acta (BBA) - General Subjects, 2009

The process of physiological decline leading to death of the individual is driven by the deteriorating capacity to withstand extrinsic and intrinsic hazards, resulting in damage accumulation with age. The dynamic changes with time of the network governing the outcome of misfolded proteins, exemplifying as intrinsic hazards, is considered here as a paradigm of aging. The main features of the network, namely, the non-linear increase of damage and the presence of amplifying feedback loops within the system are presented through a survey of the different components of the network and related cellular processes in aging and disease.

Role of Carbonyl Modifications on Aging-Associated Protein Aggregation

Scientific Reports, 2016

Protein aggregation is a common biological phenomenon, observed in different physiological and pathological conditions. Decreased protein solubility and a tendency to aggregate is also observed during physiological aging but the causes are currently unknown. Herein we performed a biophysical separation of aging-related high molecular weight aggregates, isolated from the bone marrow and splenic cells of aging mice and followed by biochemical and mass spectrometric analysis. The analysis indicated that compared to younger mice an increase in protein post-translational carbonylation was observed. The causative role of these modifications in inducing protein misfolding and aggregation was determined by inducing carbonyl stress in young mice, which recapitulated the increased protein aggregation observed in old mice. Altogether our analysis indicates that oxidative stress-related posttranslational modifications accumulate in the aging proteome and are responsible for increased protein aggregation and altered cell proteostasis. Protein aggregation is a general terminology used to describe the association of proteins into larger assemblies following loss of secondary, tertiary or quaternary structure and often loss of biological activity 1. Protein aggregation is a common biological phenomenon associated with the inability of the cell to maintain homeostasis of the proteome (proteostasis) 1. Under physiological conditions, the tendency of de novo synthesized unfolded proteins to aggregate is regulated by several chaperones that aid in their folding 2,3. Soluble aggregation is also commonly observed in ubiquitinated unfolded proteins before proteasome degradation or in damaged proteins before translocation into lysosomes by chaperone-mediated autophagy 4-6. Additionally, temporal changes to cellular homeostasis (temperature, pH, water content and salt/ions concentration) can induce transitory protein unfolding and soluble aggregation 1. During pathological conditions, protein aggregation is a common occurrence giving rise to the group of diseases collectively known as protein conformational diseases. In many degenerative diseases of the CNS, such as Alzheimer's, Parkinson's and Huntington's disease protein aggregation is a common pathological hallmark due to amino acid mutation and changes in the primary structure of the proteins 7-11. Size-wise, aggregates can range considerably, from protein oligomers up to visible cytosolic inclusions, known as the aggresome 12. The sub cellular location of these aggregates can also vary, from perinuclear to peri-endolasmic reticulum (ER) or intra-endosomal. Perinuclear aggregates (aggresomes) co-localize with the microtubule organizing center and mostly contain terminally aggregated proteins 12 , whereas ER-associated aggregates are mostly formed by soluble aggregates of ubiquitinated misfolded proteins 3 and endosomal aggregates are inclusions that co-localize with autophagic markers 13-15. The functional consequences of aggregation are also variable, from up-regulation of autophagy 16 , to cellular apoptosis due to aggregate-related cytotoxicity. Recently, it has been reported that during physiological aging proteostasis gradually becomes compromised and several hundred proteins tend to become more insoluble and aggregate 17,18. A few of these proteins have been shown to have common biochemical and biological properties, such as a primary structure with amino acids stretches often found in proteins associated with neurodegenerative diseases and a secondary structure with

The Biology of Proteostasis in Aging and Disease

Loss of protein homeostasis (proteostasis) is a common feature of aging and disease that is characterized by the appearance of nonnative protein aggregates in various tissues. Protein aggregation is routinely suppressed by the proteostasis network (PN), a collection of macromolecular machines that operate in diverse ways to maintain proteome integrity across subcellular compartments and between tissues to ensure a healthy life span. Here, we review the composition, function, and organizational properties of the PN in the context of individual cells and entire organisms and discuss the mechanisms by which disruption of the PN, and related stress response pathways, contributes to the initiation and progression of disease. We explore emerging evidence that disease susceptibility arises from early changes in the composition and activity of the PN and propose that a more complete understanding of the temporal and spatial properties of the PN will enhance our ability to develop effective treatments for protein conformational diseases.

Tissue-specific landscape of protein aggregation and quality control in an aging vertebrate

2022

SUMMARYProtein aggregation is a hallmark of age-related neurodegeneration. Yet, aggregation during normal aging and in tissues other than the brain is poorly understood. Here we leverage the African turquoise killifish to systematically profile protein aggregates in seven tissues of an aging vertebrate. Age-dependent aggregation is strikingly tissue-specific, and not simply driven by protein expression differences. Experimental interrogation, combined with machine learning, indicates that this specificity is linked to both protein-autonomous biophysical features and tissue-selective alterations in protein quality control. Co-aggregation of protein quality control machinery during aging may further reduce proteostasis capacity, exacerbating aggregate burden. A segmental progeria model with accelerated aging in specific tissues exhibits selectively increased aggregation in these same tissues. Intriguingly, many age-related protein aggregates arise in wild-type proteins that, when muta...

Protein stress and stress proteins: implications in aging and disease

2007

Environmantal stress induces damage that activates an adaptive response in any organism. The cellular stress response is based on the induction of cytoprotective proteins, the so called stress or heat shock proteins. The stress response as well as stress proteins are ubiquitous, highly conserved mechanism, and genes, respectively, already present in prokaryotes. Chaperones protect the proteome against conformational damage, promoting the function of protein networks. Protein damage takes place during aging and in several degenerative diseases, and presents a threat to overload the cellular defense mechanisms. The preservation of a robust stress response and protein disposal is indispensable for health and longevity. This review summarizes the present knowledge of protein damage, turnover, and the stress response in aging and degenerative diseases.

Accumulation of modified proteins and aggregate formation in aging

Experimental gerontology, 2014

Increasing cellular damage during the aging process is considered to be one factor limiting the lifespan of organisms. Besides the DNA and lipids, proteins are frequent targets of non-enzymatic modifications by reactive substances including oxidants and glycating agents. Non-enzymatic protein modifications may alter the protein structure often leading to impaired functionality. Although proteolytic systems ensure the removal of modified proteins, the activity of these proteases was shown to decline during the aging process. The additional age-related increase of reactive compounds as a result of impaired antioxidant systems leads to the accumulation of damaged proteins and the formation of protein aggregates. Both, non-enzymatic modified proteins and protein aggregates impair cellular functions and tissue properties by a variety of mechanisms. This is increasingly important in aging and age-related diseases. In this review, we will give an overview on oxidation and glycation of prot...

Protein Structure and Function in Aging and Age-Related Diseases

2020

Aging is not a disease, but a complex process driven by diverse molecular pathways and biochemical events. It is usually seen as the reason of progressive loss of physiological functions that ultimately lead to death. Every species is associated with an average life expectancy, and therefore it is plausible to think that aging is programmed in our genes. Genes exert their effects by gene expression that is coupled with protein synthesis. Proteins are most abundant and structurally diverse, perform wide variety of roles, and in part maintain functional stability and homeostasis of cells. Protein misfolding, aggregation, or an alteration in protein–protein/nucleic acid/lipid interactions and modifications has the potential to disturb many metabolic pathways. During aging such alterations are accelerated and accumulations of altered proteins are correlated with age- and disease-related pathologies. Therefore, it is critical to identify and understand proteomic spectrum and its function...

Proteostasis and the aging proteome in health and disease

The journals of gerontology. Series A, Biological sciences and medical sciences, 2014

The maintenance of the proteome is essential to preserve cell functionality and the ability to respond and adapt to the changing environment. This is regulated by the proteostasis network, a dedicated set of molecular components comprised of molecular chaperones and protein clearance mechanisms, regulated by cell stress signaling pathways, that prevents the toxicity associated with protein misfolding and accumulation of toxic aggregates in different subcellular compartments and tissues. The efficiency of the proteostasis network declines with age and this failure in protein homeostasis has been proposed to underlie the basis of common age-related human disorders. The current advances in the understanding of the mechanisms and regulation of proteostasis and of the different types of digressions in this process in aging have turned the attention toward the therapeutic opportunities offered by the restoration of proteostasis in age-associated degenerative diseases. Here, we discuss som...