RESUMO
Heat Shock Factor 1 (HSF1) is best known as the master transcriptional regulator of the heat-shock response (HSR), a conserved adaptive mechanism critical for protein homeostasis (proteostasis). Combining a genome-wide RNAi library with an HSR reporter, we identified Jumonji domain-containing protein 6 (JMJD6) as an essential mediator of HSF1 activity. In follow-up studies, we found that JMJD6 is itself a noncanonical transcriptional target of HSF1 which acts as a critical regulator of proteostasis. In a positive feedback circuit, HSF1 binds and promotes JMJD6 expression, which in turn reduces heat shock protein 70 (HSP70) R469 monomethylation to disrupt HSP70-HSF1 repressive complexes resulting in enhanced HSF1 activation. Thus, JMJD6 is intricately wired into the proteostasis network where it plays a critical role in cellular adaptation to proteotoxic stress.
Assuntos
Proteínas de Choque Térmico HSP70 , Fatores de Transcrição de Choque Térmico , Resposta ao Choque Térmico , Histona Desmetilases com o Domínio Jumonji , Proteostase , Humanos , Fatores de Transcrição de Choque Térmico/metabolismo , Fatores de Transcrição de Choque Térmico/genética , Resposta ao Choque Térmico/fisiologia , Histona Desmetilases com o Domínio Jumonji/metabolismo , Histona Desmetilases com o Domínio Jumonji/genética , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico HSP70/genética , Proteostase/fisiologia , Retroalimentação Fisiológica , Adaptação Fisiológica , Células HEK293 , Estresse ProteotóxicoRESUMO
Ubiquitin-fold modifier 1 (UFM1) is covalently conjugated to protein substrates via a cascade of enzymatic reactions, a process known as UFMylation. UFMylation orchestrates an array of vital biological functions, including maintaining endoplasmic reticulum (ER) homeostasis, facilitating protein biogenesis, promoting cellular differentiation, regulating DNA damage response, and participating in cancer-associated signaling pathways. UFMylation has rapidly evolved into one of the forefront research areas within the last few years, yet much remains to be uncovered. In this review, first, UFMylation and its cellular functions associated with diseases are briefly introduced. Then, we summarize the proteomic approaches for identifying UFMylation substrates and explore the impact of UFMylation on gene transcription, protein translation, and maintenance of ER homeostasis. Next, we highlight the intricate regulation between UFMylation and two protein degradation pathways, the ubiquitin-proteasome system and the autophagy-lysosome pathway, and explore the potential of UFMylation system as a drug target. Finally, we discuss emerging perspectives in the UFMylation field. This review may provide valuable insights for drug discovery targeting the UFMylation system.
Assuntos
Processamento de Proteína Pós-Traducional , Proteostase , Humanos , Proteostase/fisiologia , Animais , Autofagia/fisiologia , Retículo Endoplasmático/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , ProteínasRESUMO
Little is known about the possibility of reversing age-related biological changes when they have already occurred. To explore this, we have characterized the effects of reducing insulin/IGF-1 signaling (IIS) during old age. Reduction of IIS throughout life slows age-related decline in diverse species, most strikingly in the nematode Caenorhabditis elegans. Here we show that even at advanced ages, auxin-induced degradation of DAF-2 in single tissues, including neurons and the intestine, is still able to markedly increase C. elegans lifespan. We describe how reversibility varies among senescent changes. While senescent pathologies that develop in mid-life were not reversed, there was a rejuvenation of the proteostasis network, manifesting as a restoration of the capacity to eliminate otherwise intractable protein aggregates that accumulate with age. Moreover, resistance to several stressors was restored. These results support several new conclusions. (1) Loss of resilience is not solely a consequence of pathologies that develop in earlier life. (2) Restoration of proteostasis and resilience by inhibiting IIS is a plausible cause of the increase in lifespan. And (3), most interestingly, some aspects of the age-related transition from resilience to frailty can be reversed to a certain extent. This raises the possibility that the effect of IIS and related pathways on resilience and frailty during aging in higher animals might possess some degree of reversibility.
Assuntos
Envelhecimento , Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Longevidade , Proteostase , Receptor de Insulina , Transdução de Sinais , Animais , Longevidade/fisiologia , Proteostase/fisiologia , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Receptor de Insulina/metabolismo , Envelhecimento/fisiologia , Envelhecimento/metabolismo , Transdução de Sinais/fisiologia , Fator de Crescimento Insulin-Like I/metabolismo , Insulina/metabolismoRESUMO
The integrated stress response (ISR) is a highly conserved biochemical pathway that regulates protein synthesis. The ISR is activated in response to diverse stressors to restore cellular homeostasis. As such, the ISR is implicated in a wide range of diseases, including brain disorders. However, in the brain, the ISR also has potent influence on processes beyond proteostasis, namely synaptic plasticity, learning and memory. Thus, in the setting of brain diseases, ISR activity may have dual effects on proteostasis and synaptic function. In this review, we consider the ISR's contribution to brain disorders through the lens of its potential effects on synaptic plasticity. From these examples, we illustrate that at times ISR activity may be a "double-edged sword". We also highlight its potential as a therapeutic target to improve circuit function in brain diseases independent of its role in disease pathogenesis.
Assuntos
Encefalopatias , Plasticidade Neuronal , Proteostase , Sinapses , Humanos , Proteostase/fisiologia , Animais , Sinapses/fisiologia , Sinapses/metabolismo , Sinapses/patologia , Encefalopatias/metabolismo , Encefalopatias/fisiopatologia , Plasticidade Neuronal/fisiologia , Estresse Fisiológico/fisiologia , Encéfalo/metabolismoRESUMO
αSynuclein (αSyn) misfolding and aggregation frequently precedes neuronal loss associated with Parkinson's Disease (PD) and other Synucleinopathies. The progressive buildup of pathological αSyn species results from alterations on αSyn gene and protein sequence, increased local concentrations, variations in αSyn interactome and protein network. Therefore, under physiological conditions, it is mandatory to regulate αSyn proteostasis as an equilibrium among synthesis, trafficking, degradation and extracellular release. In this frame, a crucial parameter is protein half-life. It provides indications of the turnover of a specific protein and depends on mRNA synthesis and translation regulation, subcellular localization, function and clearance by the designated degradative pathways. For αSyn, the molecular mechanisms regulating its proteostasis in neurons have been extensively investigated in various cellular models, either using biochemical or imaging approaches. Nevertheless, a converging estimate of αSyn half-life has not emerged yet. Here, we discuss the challenges in studying αSyn proteostasis under physiological and pathological conditions, the advantages and disadvantages of the experimental strategies proposed so far, and the relevance of determining αSyn half-life from a translational perspective.
Assuntos
alfa-Sinucleína , Humanos , alfa-Sinucleína/metabolismo , Meia-Vida , Animais , Sinucleinopatias/metabolismo , Sinucleinopatias/patologia , Doença de Parkinson/metabolismo , Doença de Parkinson/genética , Proteostase/fisiologia , Neurônios/metabolismoRESUMO
Age is among the most potent risk factors for developing heart failure and is strongly associated with adverse outcomes. As the global population continues to age and the prevalence of heart failure rises, understanding the role of aging in the development and progression of this chronic disease is essential. Although chronologic age is on a fixed course, biological aging is more variable and potentially modifiable in patients with heart failure. This review describes the current knowledge on mechanisms of biological aging that contribute to the pathogenesis of heart failure. The discussion focuses on 3 hallmarks of aging-impaired proteostasis, mitochondrial dysfunction, and deregulated nutrient sensing-that are currently being targeted in therapeutic development for older adults with heart failure. In assessing existing and emerging therapeutic strategies, the review also enumerates the importance of incorporating geriatric conditions into the management of older adults with heart failure and in ongoing clinical trials.
Assuntos
Envelhecimento , Insuficiência Cardíaca , Humanos , Insuficiência Cardíaca/fisiopatologia , Envelhecimento/fisiologia , Proteostase/fisiologia , IdosoRESUMO
Disturbances in protein phase transitions promote protein aggregationâa neurodegeneration hallmark. The modular Ran-binding protein 2 (Ranbp2) is a cytosolic molecular hub for rate-limiting steps of phase transitions of Ran-GTP-bound protein ensembles exiting nuclear pores. Chaperones also regulate phase transitions and proteostasis by suppressing protein aggregation. Ranbp2 haploinsufficiency promotes the age-dependent neuroprotection of the chorioretina against phototoxicity by proteostatic regulations of neuroprotective substrates of Ranbp2 and by suppressing the buildup of polyubiquitylated substrates. Losses of peptidyl-prolyl cis-trans isomerase (PPIase) and chaperone activities of the cyclophilin domain (CY) of Ranbp2 recapitulate molecular effects of Ranbp2 haploinsufficiency. These CY impairments also stimulate deubiquitylation activities and phase transitions of 19S cap subunits of the 26S proteasome that associates with Ranbp2. However, links between CY moonlighting activity, substrate ubiquitylation, and proteostasis remain incomplete. Here, we reveal the Ranbp2 regulation of small heat shock chaperonesâcrystallins in the chorioretina by proteomics of mice with total or selective modular deficits of Ranbp2. Specifically, loss of CY PPIase of Ranbp2 upregulates αA-Crystallin, which is repressed in adult nonlenticular tissues. Conversely, impairment of CY's chaperone activity opposite to the PPIase pocket downregulates a subset of αA-Crystallin's substrates, γ-crystallins. These CY-dependent effects cause age-dependent and chorioretinal-selective declines of ubiquitylated substrates without affecting the chorioretinal morphology. A model emerges whereby inhibition of Ranbp2's CY PPIase remodels crystallins' expressions, subdues molecular aging, and preordains the chorioretina to neuroprotection by augmenting the chaperone capacity and the degradation of polyubiquitylated substrates against proteostatic impairments. Further, the druggable Ranbp2 CY holds pan-therapeutic potential against proteotoxicity and neurodegeneration.
Assuntos
Ciclofilinas , Chaperonas Moleculares , Complexo de Proteínas Formadoras de Poros Nucleares , Peptidilprolil Isomerase , Proteostase , Animais , Chaperonas Moleculares/metabolismo , Camundongos , Ciclofilinas/metabolismo , Proteostase/fisiologia , Peptidilprolil Isomerase/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Cristalinas/metabolismoRESUMO
Amyotrophic lateral sclerosis damages proteostasis, affecting spinal and upper motor neurons earlier than a subset of cranial motor neurons. To aid disease understanding, we exposed induced cranial and spinal motor neurons (iCrMNs and iSpMNs) to proteotoxic stress, under which iCrMNs showed superior survival, quantifying the transcriptome and proteome for >8,200 genes at 0, 12, and 36 h. Two-thirds of the proteome showed cell-type differences. iSpMN-enriched proteins related to DNA/RNA metabolism, and iCrMN-enriched proteins acted in the endoplasmic reticulum (ER)/ER chaperone complex, tRNA aminoacylation, mitochondria, and the plasma/synaptic membrane, suggesting that iCrMNs expressed higher levels of proteins supporting proteostasis and neuronal function. When investigating the increased proteasome levels in iCrMNs, we showed that the activity of the 26S proteasome, but not of the 20S proteasome, was higher in iCrMNs than in iSpMNs, even after a stress-induced decrease. We identified Ublcp1 as an iCrMN-specific regulator of the nuclear 26S activity.
Assuntos
Esclerose Lateral Amiotrófica , Proteostase , Humanos , Proteostase/fisiologia , Proteoma/metabolismo , Neurônios Motores/metabolismo , Esclerose Lateral Amiotrófica/genética , Retículo Endoplasmático/metabolismo , Estresse do Retículo EndoplasmáticoRESUMO
The molecular motor myosin is post-translationally modified in its globular head, its S2 hinge, and its thick filament domain during human skeletal muscle aging. To determine the importance of such modifications, we performed an integrative analysis of transgenic Drosophila melanogaster expressing myosin containing post-translational modification mimic mutations. We determined effects on muscle function, myofibril structure, and myosin biochemistry. Modifications in the homozygous state decreased jump muscle function by a third at 3 weeks of age and reduced indirect flight muscle function to negligible levels in young flies, with severe effects on flight muscle myofibril assembly and/or maintenance. Expression of mimic mutations in the heterozygous state or in a wild-type background yielded significant, but less severe, age-dependent effects upon flight muscle structure and function. Modification of the residue in the globular head disabled ATPase activity and in vitro actin filament motility, whereas the S2 hinge mutation reduced actin-activated ATPase activity by 30%. The rod modification diminished filament formation in vitro. The latter mutation also reduced proteostasis, as demonstrated by enhanced accumulation of polyubiquitinated proteins. Overall, we find that mutation of amino acids at sites that are chemically modified during human skeletal muscle aging can disrupt myosin ATPase, myosin filament formation, and/or proteostasis, providing a mechanistic basis for the observed muscle defects. We conclude that age-specific post-translational modifications present in human skeletal muscle are likely to act in a dominant fashion to affect muscle structure and function and may therefore be implicated in degeneration and dysfunction associated with sarcopenia.
Assuntos
Envelhecimento , Drosophila melanogaster , Músculo Esquelético , Miofibrilas , Processamento de Proteína Pós-Traducional , Proteostase , Animais , Miofibrilas/metabolismo , Proteostase/fisiologia , Drosophila melanogaster/metabolismo , Humanos , Envelhecimento/metabolismo , Músculo Esquelético/metabolismo , Miosinas de Músculo Esquelético/metabolismo , Miosinas de Músculo Esquelético/genética , Animais Geneticamente ModificadosRESUMO
SUMMARYHeat shock protein 90 (Hsp90) participates in proteostasis by facilitating protein folding, activation, disaggregation, prevention of aggregation, degradation, and protection against degradation of various cellular proteins. It is highly conserved from bacteria to humans. In bacteria, protein remodeling by Hsp90 involves collaboration with the Hsp70 molecular chaperone and Hsp70 cochaperones. In eukaryotes, protein folding by Hsp90 is more complex and involves collaboration with many Hsp90 cochaperones as well as Hsp70 and Hsp70 cochaperones. This review focuses primarily on bacterial Hsp90 and highlights similarities and differences between bacterial and eukaryotic Hsp90. Seminal research findings that elucidate the structure and the mechanisms of protein folding, disaggregation, and reactivation promoted by Hsp90 are discussed. Understanding the mechanisms of bacterial Hsp90 will provide fundamental insight into the more complex eukaryotic chaperone systems.
Assuntos
Bactérias , Proteínas de Bactérias , Proteínas de Choque Térmico HSP90 , Dobramento de Proteína , Proteínas de Choque Térmico HSP90/metabolismo , Proteínas de Bactérias/metabolismo , Bactérias/metabolismo , Humanos , Estresse Fisiológico , Proteostase/fisiologia , Proteínas de Choque Térmico HSP70/metabolismo , Chaperonas Moleculares/metabolismoRESUMO
Imbalances in mitochondrial proteostasis are associated with pathologic mitochondrial dysfunction implicated in etiologically diverse diseases. This has led to considerable interest in defining the mechanisms responsible for regulating mitochondria in response to mitochondrial stress. Numerous stress-responsive signaling pathways have been suggested to regulate mitochondria in response to proteotoxic stress. These include the integrated stress response (ISR), the heat shock response (HSR), and the oxidative stress response (OSR). Here, we define the stress signaling pathways activated in response to chronic mitochondrial proteostasis perturbations by monitoring the expression of sets of genes regulated downstream of each of these signaling pathways in published Perturb-seq datasets from K562 cells CRISPRi-depleted of mitochondrial proteostasis factors. Interestingly, we find that the ISR is preferentially activated in response to chronic, genetically-induced mitochondrial proteostasis stress, with no other pathway showing significant activation. Further, we demonstrate that CRISPRi depletion of other mitochondria-localized proteins similarly shows preferential activation of the ISR relative to other stress-responsive signaling pathways. These results both establish our gene set profiling approach as a viable strategy to probe stress responsive signaling pathways induced by perturbations to specific organelles and identify the ISR as the predominant stress-responsive signaling pathway activated in response to chronic disruption of mitochondrial proteostasis.
Assuntos
Mitocôndrias , Proteostase , Proteostase/fisiologia , Mitocôndrias/metabolismo , Estresse Oxidativo , Transdução de Sinais/fisiologia , Resposta ao Choque Térmico , Proteínas Mitocondriais/metabolismoRESUMO
Protein is fundamental to life, as it generates protein variants. The maintenance of a dynamic equilibrium in these protein variants, known as protein homeostasis, is crucial for cellular function. Various factors, both endogenous and exogenous, can disrupt protein homeostasis during protein synthesis. These factors include translational error, and biological functions mediated by regulatory factors, and more. When cell accumulate proteins with folding errors, it impairs protein homeostasis, leading to the development of related diseases. In response to protein folding errors, multiple monitoring mechanisms are activated to mediate pathways that sustain the dynamic equilibrium. This review highlights the complex relationships within the proteostasis network, which are influenced by a variety of factors. These insights potentially provide new directions for studying diseases caused by protein synthesis errors.
Assuntos
Dobramento de Proteína , Proteostase , Proteostase/fisiologia , Proteínas/genética , Proteínas/metabolismo , Biossíntese de ProteínasRESUMO
Aging is a major risk factor for many diseases. Recent studies have shown that age-related disruption of proteostasis leads to the accumulation of abnormal proteins and that dysfunction of the two major intracellular proteolytic pathways, the ubiquitin-proteasome pathway, and the autophagy-lysosome pathway, is largely responsible for this process. Conversely, it has been shown that activation of these proteolytic pathways may contribute to lifespan extension and suppression of pathological conditions, making it a promising intervention for anti-aging. This review provides an overview of the important role of intracellular protein degradation in aging and summarizes how the disruption of proteostasis is involved in age-related diseases.
Assuntos
Envelhecimento , Autofagia , Senescência Celular , Complexo de Endopeptidases do Proteassoma , Proteólise , Proteostase , Humanos , Senescência Celular/fisiologia , Envelhecimento/metabolismo , Animais , Autofagia/fisiologia , Proteostase/fisiologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina/metabolismo , Lisossomos/metabolismoRESUMO
Proteostasis, the maintenance of proper protein folding, stability, and degradation within cells, is fundamental for cellular function. Two key players in this intricate cellular process are macroautophagy/autophagy and chaperoning of nascent proteins. Here, we explore the crosstalk between autophagy and the HSP90 chaperone in maintaining proteostasis, highlighting their interplay and significance in cellular homeostasis.Abbreviation: HSP90: heat shock protein 90; PTMs: post-translational modifications.
Assuntos
Autofagia , Proteínas de Choque Térmico HSP90 , Proteostase , Animais , Humanos , Autofagia/fisiologia , Proteínas de Choque Térmico HSP90/metabolismo , Chaperonas Moleculares/metabolismo , Processamento de Proteína Pós-Traducional , Proteostase/fisiologiaRESUMO
Preterm white matter injury (WMI) is a demyelinating disease with high incidence and mortality in premature infants. Oligodendrocyte cells (OLs) are a specialized glial cell that produces myelin proteins and adheres to the axons providing energy and metabolic support which susceptible to endoplasmic reticulum protein quality control. Disruption of cellular protein homeostasis led to OLs dysfunction and cell death, immediately, the unfolded protein response (UPR) activated to attempt to restore the protein homeostasis via IRE1/XBP1s, PERK/eIF2α and ATF6 pathway that reduced protein translation, strengthen protein-folding capacity, and degraded unfolding/misfolded protein. Moreover, recent works have revealed the conspicuousness function of ER signaling pathways in regulating influenced factors such as calcium homeostasis, mitochondrial reactive oxygen generation, and autophagy activation to regulate protein hemostasis and improve the myelination function of OLs. Each of the regulation modes and their corresponding molecular mechanisms provides unique opportunities and distinct perspectives to obtain a deep understanding of different actions of ER stress in maintaining OLs' health and function. Therefore, our review focuses on summarizing the current understanding of ER stress on OLs' protein homeostasis micro-environment in myelination during white matter development, as well as the pathophysiology of WMI, and discussing the further potential experimental therapeutics targeting these factors that restore the function of the UPR in OLs myelination function.
Assuntos
Estresse do Retículo Endoplasmático , Recém-Nascido Prematuro , Oligodendroglia , Substância Branca , Humanos , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Estresse do Retículo Endoplasmático/fisiologia , Substância Branca/metabolismo , Substância Branca/patologia , Animais , Recém-Nascido , Proteostase/fisiologia , Bainha de Mielina/metabolismo , Homeostase/fisiologia , Resposta a Proteínas não Dobradas/fisiologiaRESUMO
This preface introduces the Journal of Neurochemistry Special Issue on Brain Proteostasis. Adequate control of protein homeostasis, or proteostasis, has been at the center stage of brain physiology, and its deregulation may contribute to brain diseases, including several neuropsychiatric and neurodegenerative conditions. Therefore, delineating the processes underlying protein synthesis, folding, stability, function, and degradation in brain cells is key to promoting brain function and identifying effective therapeutic options for neurological disorders. This special issue comprises four review articles and four original articles covering the roles of protein homeostasis in several mechanisms that are of relevance to sleep, depression, stroke, dementia, and COVID-19. Thus, these articles highlight different aspects of proteostasis regulation in the brain and present important evidence on this growing and exciting field.
Assuntos
COVID-19 , Doenças Neurodegenerativas , Deficiências na Proteostase , Humanos , Proteostase/fisiologia , Doenças Neurodegenerativas/metabolismo , Encéfalo/metabolismoRESUMO
Aging is a topic of paramount importance in an increasingly elderly society and has been the focus of extensive research. Protein homeostasis (proteostasis) decline is a hallmark in aging and several age-related diseases, but which specific proteins and mechanisms are involved in proteostasis (de)regulation during the aging process remain largely unknown. Here, we used different text-mining tools complemented with protein-protein interaction data to address this complex topic. Analysis of the integrated protein interaction networks identified novel proteins and pathways associated to proteostasis mechanisms and aging or age-related disorders, indicating that this approach is useful to identify previously unknown links and for retrieving information of potential novel biomarkers or therapeutic targets.
Assuntos
Deficiências na Proteostase , Proteostase , Humanos , Idoso , Proteostase/fisiologia , Dobramento de Proteína , Envelhecimento/fisiologia , Mineração de DadosRESUMO
During aging, animals experience a decline in proteostasis activity, including loss of stress-response activation, culminating in the accumulation of misfolded proteins and toxic aggregates, which are causal in the onset of some chronic diseases. Finding genetic and pharmaceutical treatments that can increase organismal proteostasis and lengthen life is an ongoing goal of current research. The regulation of stress responses by cell non-autonomous mechanisms appears to be a potent way to impact organismal healthspan. In this Review, we cover recent findings in the intersection of proteostasis and aging, with a special focus on articles and preprints published between November 2021 and October 2022. A significant number of papers published during this time increased our understanding of how cells communicate with each other during proteotoxic stress. Finally, we also draw attention to emerging datasets that can be explored to generate new hypotheses that explain age-related proteostasis collapse.
Assuntos
Envelhecimento , Proteostase , Animais , Proteostase/fisiologia , Envelhecimento/metabolismo , Proteínas/metabolismoRESUMO
The protein dyshomeostasis is identified as the hallmark of many age-related neurodegenerative disorders including Parkinson's disease (PD). The diseased brain shows the deposition of Lewy bodies composed of α-synuclein protein aggregates. Functional proteostasis is characterized by the well-coordinated signaling network constituting unfolded protein response (UPR), the ubiquitin-proteasome system (UPS), and the autophagy-lysosome pathway (ALP). These networks ensure proper synthesis, folding, confirmation, and degradation of protein i.e., α-synuclein protein in PD. The proper functioning the of intricately woven proteostasis network is quite resilient to sustain under the influence of stressors. The synuclein protein turnover is hugely influenced by the autosomal dominant, recessive, and X-linked mutational changes of a gene involved in UPR, UPS, and ALP. The methylation, acetylation-related epigenetic modifications of DNA and histone proteins along with microRNA-mediated transcriptional changes also lead to extensive proteostasis dysregulation. The result of defective proteostasis is the deposition of many proteins which start appearing in the biofluids and can be identified as potential biomarkers for early diagnosis of PD. The therapeutic intervention targeted at different strata of proteostasis machinery holds great possibilities for delaying the age-related accumulation of pathological hallmarks.
Assuntos
Doença de Parkinson , Proteostase , Humanos , alfa-Sinucleína/metabolismo , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/terapia , Doença de Parkinson/diagnóstico , Doença de Parkinson/metabolismo , Doença de Parkinson/terapia , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteostase/fisiologia , Ubiquitina/metabolismo , Resposta a Proteínas não DobradasRESUMO
Healthy cells utilize a series of protein quality regulatory networks to maintain the integrity and functionality of their proteome, named as protein homeostasis (proteostasis). However, the phenomenon of proteostasis collapse, including the destruction of the balance between protein synthesis, folding and degradation, are common with aging. The main causes of age-associated proteostasis collapse are as follows: (1) the decline in transcriptional activation of stress response related pathways, (2) the reduction of proteasome and autophagy activity, and (3) ribosome pausing during translation. In addition, proteostasis is regulated mainly through chaperones, proteasomes, and autophagy systems of proteostasis network in aging. This paper mainly reviews the causes of age-associated proteostasis collapse and the pathways of proteostasis regulation, which may open the way to explore aging studies and solve aging problems.