Showing papers on "Proteotoxicity published in 2021"

A guide to understanding endoplasmic reticulum stress in metabolic disorders

Abstract: Background The global rise of metabolic disorders, such as obesity, type 2 diabetes, and cardiovascular disease, demands a thorough molecular understanding of the cellular mechanisms that govern health or disease. The endoplasmic reticulum (ER) is a key organelle for cellular function and metabolic adaptation and, therefore disturbed ER function, known as “ER stress,” is a key feature of metabolic disorders. Scope of review As ER stress remains a poorly defined phenomenon, this review provides a general guide to understanding the nature, etiology, and consequences of ER stress in metabolic disorders. We define ER stress by its type of stressor, which is driven by proteotoxicity, lipotoxicity, and/or glucotoxicity. We discuss the implications of ER stress in metabolic disorders by reviewing evidence implicating ER phenotypes and organelle communication, protein quality control, calcium homeostasis, lipid and carbohydrate metabolism, and inflammation as key mechanisms in the development of ER stress and metabolic dysfunction. Major conclusions In mammalian biology, ER is a phenotypically and functionally diverse platform for nutrient sensing, which is critical for cell type-specific metabolic control by hepatocytes, adipocytes, muscle cells, and neurons. In these cells, ER stress is a distinct, transient state of functional imbalance, which is usually resolved by the activation of adaptive programs such as the unfolded protein response (UPR), ER-associated protein degradation (ERAD), or autophagy. However, challenges to proteostasis also impact lipid and glucose metabolism and vice versa. In the ER, sensing and adaptive measures are integrated and failure of the ER to adapt leads to aberrant metabolism, organelle dysfunction, insulin resistance, and inflammation. In conclusion, the ER is intricately linked to a wide spectrum of cellular functions and is a critical component in maintaining and restoring metabolic health.

Flavonoids: Potential Candidates for the Treatment of Neurodegenerative Disorders.

Abstract: Neurodegenerative disorders, such as Parkinson's disease (PD), Alzheimer's disease (AD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), are the most concerning disorders due to the lack of effective therapy and dramatic rise in affected cases. Although these disorders have diverse clinical manifestations, they all share a common cellular stress response. These cellular stress responses including neuroinflammation, oxidative stress, proteotoxicity, and endoplasmic reticulum (ER)-stress, which combats with stress conditions. Environmental stress/toxicity weakened the cellular stress response which results in cell damage. Small molecules, such as flavonoids, could reduce cellular stress and have gained much attention in recent years. Evidence has shown the potential use of flavonoids in several ways, such as antioxidants, anti-inflammatory, and anti-apoptotic, yet their mechanism is still elusive. This review provides an insight into the potential role of flavonoids against cellular stress response that prevent the pathogenesis of neurodegenerative disorders.

Pulse-Chase Proteomics of the App Knockin Mouse Models of Alzheimer’s Disease Reveals that Synaptic Dysfunction Originates in Presynaptic Terminals

Abstract: Compromised protein homeostasis underlies accumulation of plaques and tangles in Alzheimer's disease (AD). To observe protein turnover at early stages of amyloid beta (Aβ) proteotoxicity, we performed pulse-chase proteomics on mouse brains in three genetic models of AD that knock in alleles of amyloid precursor protein (APP) prior to the accumulation of plaques and during disease progression. At initial stages of Aβ accumulation, the turnover of proteins associated with presynaptic terminals is selectively impaired. Presynaptic proteins with impaired turnover, particularly synaptic vesicle (SV)-associated proteins, have elevated levels, misfold in both a plaque-dependent and -independent manner, and interact with APP and Aβ. Concurrent with elevated levels of SV-associated proteins, we found an enlargement of the SV pool as well as enhancement of presynaptic potentiation. Together, our findings reveal that the presynaptic terminal is particularly vulnerable and represents a critical site for manifestation of initial AD etiology. A record of this paper's transparent peer review process is included in the Supplemental Information.

The eIF2α kinase HRI in innate immunity, proteostasis, and mitochondrial stress.

Abstract: The integrated stress response (ISR) is an evolutionary conserved stress response pathway that leads to a global arrest in translation as well as to the expression of specific genes, such as the transcription factor ATF4, to promote cellular recovery. The central nexus of this pathway is the phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α) by one of the four eIF2α kinases that sense specific cellular stressors. The heme-regulated inhibitor (HRI) is one of these kinases, and it was initially reported to be activated in response to heme deprivation. Nevertheless, further studies have established that cytosolic proteotoxicity, resulting from oxidative or osmotic stress, heat shock, and proteasome inhibition, is the predominant trigger for HRI to induce the ISR. In this review, we present newly identified functions of HRI in innate immunity, proteostasis, and mitochondrial stress. Indeed, HRI-mediated signaling defines a novel cytosolic unfolded protein response (cUPR) required for the proper formation of some innate immune signalosomes and the control of toxic protein aggregates, and this eIF2α kinase also serves as a relay for mitonuclear communication after a mitochondrial stress.

Colonization of the Caenorhabditis elegans gut with human enteric bacterial pathogens leads to proteostasis disruption that is rescued by butyrate.

Abstract: Protein conformational diseases are characterized by misfolding and toxic aggregation of metastable proteins, often culminating in neurodegeneration. Enteric bacteria influence the pathogenesis of neurodegenerative diseases; however, the complexity of the human microbiome hinders our understanding of how individual microbes influence these diseases. Disruption of host protein homeostasis, or proteostasis, affects the onset and progression of these diseases. To investigate the effect of bacteria on host proteostasis, we used Caenorhabditis elegans expressing tissue-specific polyglutamine reporters that detect changes in the protein folding environment. We found that colonization of the C. elegans gut with enteric bacterial pathogens disrupted proteostasis in the intestine, muscle, neurons, and the gonad, while the presence of bacteria that conditionally synthesize butyrate, a molecule previously shown to be beneficial in neurodegenerative disease models, suppressed aggregation and the associated proteotoxicity. Co-colonization with this butyrogenic strain suppressed bacteria-induced protein aggregation, emphasizing the importance of microbial interaction and its impact on host proteostasis. Further experiments demonstrated that the beneficial effect of butyrate depended on the bacteria that colonized the gut and that this protective effect required SKN-1/Nrf2 and DAF-16/FOXO transcription factors. We also found that bacteria-derived protein aggregates contribute to the observed disruption of host proteostasis. Together, these results reveal the significance of enteric infection and gut dysbiosis on the pathogenesis of protein conformational diseases and demonstrate the potential of using butyrate-producing microbes as a preventative and treatment strategy for neurodegenerative disease.

Roles of CNC Transcription Factors NRF1 and NRF2 in Cancer.

Abstract: Cancer cells exhibit unique metabolic features and take advantage of them to enhance their survival and proliferation. While the activation of NRF2 (nuclear factor erythroid 2-like 2; NFE2L2), a CNC (cap'n'collar) family transcription factor, is effective for the prevention and alleviation of various diseases, NRF2 contributes to cancer malignancy by promoting aggressive tumorigenesis and conferring therapeutic resistance. NRF2-mediated metabolic reprogramming and increased antioxidant capacity underlie the malignant behaviors of NRF2-activated cancer cells. Another member of the CNC family, NRF1, plays a key role in the therapeutic resistance of cancers. Since NRF1 maintains proteasome activity by inducing proteasome subunit genes in response to proteasome inhibitors, NRF1 protects cancer cells from proteotoxicity induced by anticancer proteasome inhibitors. An important metabolite that activates NRF1 is UDP-GlcNAc (uridine diphosphate N-acetylglucosamine), which is abundantly generated in many cancer cells from glucose and glutamine via the hexosamine pathway. Thus, the metabolic signatures of cancer cells are closely related to the oncogenic and tumor-promoting functions of CNC family members. In this review, we provide a brief overview of NRF2-mediated cancer malignancy and elaborate on NRF1-mediated drug resistance affected by an oncometabolite UDP-GlcNAc.

Vitexin prevents Aβ proteotoxicity in transgenic Caenorhabditis elegans model of Alzheimer's disease by modulating unfolded protein response.

Abstract: Alzheimer's disease (AD) accounts for an estimated 60% to 80% of all dementia cases. The present study is aimed at evaluating the neuroprotective efficacy of vitexin, an apigenin flavone glycoside using transgenic Caenorhabditis elegans strain (CL2006) of AD. The neuroprotective effect of vitexin was determined using physiological assays, quantitative polymerase chain reaction, and Western blotting. The results of survival and paralysis assay indicate that vitexin (200 μM) significantly extended the lifespan of the nematodes. Vitexin-treated nematodes showed a significant reduction in the expression of Aβ, ace-1, and ace-2 genes when compared to control. Further, vitexin significantly upregulated the expression of acr-8 and dnj-14, and increased the lifespan of the nematodes. Vitexin was also found to modulate the unfolded protein response genes (hsp-4, pek-1, ire-1, and xbp-1) and suppress the expression of Aβ. Overall, the results show that vitexin acts as a neuroprotective agent and protects transgenic C. elegans strains from Aβ proteotoxicity.

Blood-Brain Barrier and Neurovascular Unit In Vitro Models for Studying Mitochondria-Driven Molecular Mechanisms of Neurodegeneration.

Abstract: Pathophysiology of chronic neurodegeneration is mainly based on complex mechanisms related to aberrant signal transduction, excitation/inhibition imbalance, excitotoxicity, synaptic dysfunction, oxidative stress, proteotoxicity and protein misfolding, local insulin resistance and metabolic dysfunction, excessive cell death, development of glia-supported neuroinflammation, and failure of neurogenesis. These mechanisms tightly associate with dramatic alterations in the structure and activity of the neurovascular unit (NVU) and the blood–brain barrier (BBB). NVU is an ensemble of brain cells (brain microvessel endothelial cells (BMECs), astrocytes, pericytes, neurons, and microglia) serving for the adjustment of cell-to-cell interactions, metabolic coupling, local microcirculation, and neuronal excitability to the actual needs of the brain. The part of the NVU known as a BBB controls selective access of endogenous and exogenous molecules to the brain tissue and efflux of metabolites to the blood, thereby providing maintenance of brain chemical homeostasis critical for efficient signal transduction and brain plasticity. In Alzheimer’s disease, mitochondria are the target organelles for amyloid-induced neurodegeneration and alterations in NVU metabolic coupling or BBB breakdown. In this review we discuss understandings on mitochondria-driven NVU and BBB dysfunction, and how it might be studied in current and prospective NVU/BBB in vitro models for finding new approaches for the efficient pharmacotherapy of Alzheimer’s disease.

The long and winding road to target protein misfolding in cardiovascular diseases.

Abstract: BACKGROUND In the last decades, cardiovascular diseases (CVD) have remained the first leading cause of mortality and morbidity in the world. Although several therapeutic approaches have been introduced in the past, the development of novel treatments remains an important research goal, which is hampered by the lack of understanding of key mechanisms and targets. Emerging evidences in recent years indicate the involvement of misfolded proteins aggregation and the derailment of protein quality control in the pathogenesis of cardiovascular diseases. Several potential interventions targeting protein quality control have been translated from the bench to the bedside to effectively employ the misfolded proteins as promising therapeutic targets for cardiac diseases, but with trivial results. DESIGN In this review, we describe the recent progresses in preclinical and clinical studies of protein misfolding and compromised protein quality control by selecting and reporting studies focusing on cardiovascular diseases including cardiomyopathies, cardiac amyloidosis, atherosclerosis, atrial fibrillation and thrombosis. RESULTS In preclinical models, modulators of several molecular targets (eg heat shock proteins, unfolded protein response, ubiquitin protein system, autophagy and histone deacetylases) have been tested in various conditions with promising results although lacking an adequate transition towards clinical setting. CONCLUSIONS At present, no therapeutic strategies have been reported to attenuate proteotoxicity in patients with CVD due to a lack of specific biomarkers for pinpointing upstream events in protein folding defects at a subclinical stage of the diseases requiring an intensive collaboration between basic scientists and clinicians.

Chaperone-mediated autophagy: a gatekeeper of neuronal proteostasis.

Abstract: Different types of autophagy co-exist in all mammalian cells, however, the specific contribution of each of these autophagic pathways to the maintenance of cellular proteostasis and cellular function remains unknown. In this work, we have investigated the consequences of failure of chaperone-mediated autophagy (CMA) in neurons and compared the impact, on the neuronal proteome, of CMA loss to that of macroautophagy loss. We found that these autophagic pathways are non-redundant and that CMA is the main one responsible for maintenance of the metastable proteome (the one at risk of aggregation). We demonstrate that loss of CMA, as the one that occurs in aging, has a synergistic effect with the proteotoxicity associated with neurodegenerative conditions such as Alzheimer disease (AD) and, conversely, that, pharmacological enhancement of CMA is effective in improving both behavior and pathology in two different AD mouse models.

Proteome-Wide Profiling of Cellular Targets Modified by Dopamine Metabolites Using a Bio-Orthogonally Functionalized Catecholamine.

Abstract: Selective death of midbrain dopaminergic neurons is a hallmark pathology of Parkinson's disease (PD), but the molecular mechanisms that initiate the cascade of events resulting in neurodegeneration in PD remain unclear. Compelling evidence suggests that dysregulation of dopamine (DA) induces neuronal stress and damage responses that are operative processes in striatal degeneration preceding PD-like symptoms. Improper DA sequestration to vesicles raises cytosolic DA levels, which is rapidly converted into electrophilic dopaquinone species (DQs) that react readily with protein nucleophiles forming covalent modifications that alter the native structure and function of proteins. These so-called DA-protein adducts (DPAs) have been reported to play a role in neurotoxicity, and their abundance with respect to neurodegeneration has been linked to clinical and pathological features of PD that suggest that they play a causal role in PD pathogenesis. Therefore, characterizing DPAs is a critical first step in understanding the susceptibility of midbrain dopaminergic neurons during PD. To help achieve this goal, we report here a novel DA-mimetic (DAyne) containing a biorthogonal alkyne handle that exhibits a reactivity profile similar to DA in aqueous buffers. By linking DPAs formed with DAyne to a fluorescent reporter molecule, DPAs were visualized in fixed cells and within lysates. DAyne enabled global mapping of cellular proteins affected by DQ modification and their bioactive pathways through enrichment. Our proteomic profiling of DPAs in neuronal SH-SY5Y cells indicates that proteins susceptible to DPA formation are extant throughout the proteome, potentially influencing several diverse biological pathways involved in PD such as endoplasmic reticulum (ER) stress, cytoskeletal instability, proteotoxicity, and clathrin function. We validated that a protein involved in the ER stress pathway, protein disulfide isomerase 3 (PDIA3), which was enriched in our chemoproteomic analysis, is functionally inhibited by DA, providing evidence that dysregulated cellular DA may induce or exacerbate ER stress. Thus, DAyne provided new mechanistic insights into DA toxicity that may be observed during PD by enabling characterization of DPAs generated reproducibly at physiologically relevant quinone exposures. We anticipate our design and application of this reactivity-based probe will be generally applicable for clarifying mechanisms of metabolic quinone toxicity.

Suppression of a core metabolic enzyme dihydrolipoamide dehydrogenase (dld) protects against amyloid beta toxicity in C. elegans model of Alzheimer’s disease

Abstract: A decrease in energy metabolism is associated with Alzheimer's disease (AD), but it is not known whether the observed decrease exacerbates or protects against the disease. The importance of energy metabolism in AD is reinforced by the observation that variants of dihydrolipoamide dehydrogenase (DLD), is genetically linked to late-onset AD. To determine whether DLD is a suitable therapeutic target, we suppressed the dld-1 gene in Caenorhabditis elegans that express human Aβ peptide in either muscles or neurons. Suppression of the dld-1 gene resulted in significant restoration of vitality and function that had been degraded by Aβ pathology. This included protection of neurons and muscles cells. The observed decrease in proteotoxicity was associated with a decrease in the formation of toxic oligomers rather than a decrease in the abundance of the Aβ peptide. The mitochondrial uncoupler, carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP), which like dld-1 gene expression inhibits ATP synthesis, had no significant effect on Aβ toxicity. Proteomics data analysis revealed that beneficial effects after dld-1 suppression could be due to change in energy metabolism and activation of the pathways associated with proteasomal degradation, improved cell signaling and longevity. Thus, some features unique to dld-1 gene suppression are responsible for the therapeutic benefit. By direct genetic intervention, we have shown that acute inhibition of dld-1 gene function may be therapeutically beneficial. This result supports the hypothesis that lowering energy metabolism protects against Aβ pathogenicity and that DLD warrants further investigation as a therapeutic target.

UXT chaperone prevents proteotoxicity by acting as an autophagy adaptor for p62-dependent aggrephagy

Abstract: p62/SQSTM1 is known to act as a key mediator in the selective autophagy of protein aggregates, or aggrephagy, by steering ubiquitinated protein aggregates towards the autophagy pathway. Here, we use a yeast two-hybrid screen to identify the prefoldin-like chaperone UXT as an interacting protein of p62. We show that UXT can bind to protein aggregates as well as the LB domain of p62, and, possibly by forming an oligomer, increase p62 clustering for its efficient targeting to protein aggregates, thereby promoting the formation of the p62 body and clearance of its cargo via autophagy. We also find that ectopic expression of human UXT delays SOD1(A4V)-induced degeneration of motor neurons in a Xenopus model system, and that specific disruption of the interaction between UXT and p62 suppresses UXT-mediated protection. Together, these results indicate that UXT functions as an autophagy adaptor of p62-dependent aggrephagy. Furthermore, our study illustrates a cooperative relationship between molecular chaperones and the aggrephagy machinery that efficiently removes misfolded protein aggregates.

Structural Lessons From the Mutant Proinsulin Syndrome.

Abstract: Insight into folding mechanisms of proinsulin has been provided by analysis of dominant diabetes-associated mutations in the human insulin gene (INS). Such mutations cause pancreatic β-cell dysfunction due to toxic misfolding of a mutant proinsulin and impairment in trans of wild-type insulin secretion. Anticipated by the "Akita" mouse (a classical model of monogenic diabetes mellitus; DM), this syndrome illustrates the paradigm endoreticulum (ER) stress leading to intracellular proteotoxicity. Diverse clinical mutations directly or indirectly perturb native disulfide pairing leading to protein misfolding and aberrant aggregation. Although most introduce or remove a cysteine (Cys; leading in either case to an unpaired thiol group), non-Cys-related mutations identify key determinants of folding efficiency. Studies of such mutations suggest that the hormone's evolution has been constrained not only by structure-function relationships, but also by the susceptibility of its single-chain precursor to impaired foldability. An intriguing hypothesis posits that INS overexpression in response to peripheral insulin resistance likewise leads to chronic ER stress and β-cell dysfunction in the natural history of non-syndromic Type 2 DM. Cryptic contributions of conserved residues to folding efficiency, as uncovered by rare genetic variants, define molecular links between biophysical principles and the emerging paradigm of Darwinian medicine: Biosynthesis of proinsulin at the edge of non-foldability provides a key determinant of "diabesity" as a pandemic disease of civilization.

Unique integrated stress response sensors regulate cancer cell susceptibility when Hsp70 activity is compromised.

Abstract: Molecular chaperones, such as Hsp70, prevent proteotoxicity and maintain homeostasis. This is perhaps most evident in cancer cells, which overexpress Hsp70 and thrive even when harboring high levels of misfolded proteins. To define the response to proteotoxic challenges, we examined adaptive responses in breast cancer cells in the presence of an Hsp70 inhibitor. We discovered that the cells bin into distinct classes based on inhibitor sensitivity. Strikingly, the most resistant cells have higher autophagy levels, and autophagy was maximally activated only in resistant cells upon Hsp70 inhibition. In turn, resistance to compromised Hsp70 function required the integrated stress response transducer, GCN2, which is commonly associated with amino acid starvation. In contrast, sensitive cells succumbed to Hsp70 inhibition by activating PERK. These data reveal an unexpected route through which breast cancer cells adapt to proteotoxic insults and position GCN2 and autophagy as complementary mechanisms to ensure survival when proteostasis is compromised.

miR-1 coordinately regulates lysosomal v-ATPase and biogenesis to impact proteotoxicity and muscle function during aging.

Abstract: Muscle function relies on the precise architecture of dynamic contractile elements, which must be fine-tuned to maintain motility throughout life. Muscle is also plastic, and remodeled in response to stress, growth, neural and metabolic inputs. The conserved muscle-enriched microRNA, miR-1, regulates distinct aspects of muscle development, but whether it plays a role during aging is unknown. Here we investigated Caenorhabditis elegans miR-1 in muscle function in response to proteostatic stress. mir-1 deletion improved mid-life muscle motility, pharyngeal pumping, and organismal longevity upon polyQ35 proteotoxic challenge. We identified multiple vacuolar ATPase subunits as subject to miR-1 control, and the regulatory subunit vha-13/ATP6V1A as a direct target downregulated via its 3'UTR to mediate miR-1 physiology. miR-1 further regulates nuclear localization of lysosomal biogenesis factor HLH-30/TFEB and lysosomal acidification. Our studies reveal that miR-1 coordinately regulates lysosomal v-ATPase and biogenesis to impact muscle function and health during aging.

Suppression of DRR1 results in the accumulation of insoluble ubiquitinated proteins, which impairs drought stress tolerance

Abstract: Drought stress has detrimental effects on plants. Although the abscisic acid (ABA)-mediated drought response is well established, defensive mechanisms to cope with dehydration-induced proteotoxicity have been rarely studied. DRR1 was identified as an Arabidopsis drought-induced gene encoding an ER-localized RING-type E3 Ub ligase. Suppression of DRR1 markedly reduced tolerance to drought and proteotoxic stress without altering ABA-mediated germination and stomatal movement. Proteotoxicity- and dehydration-induced insoluble ubiquitinated protein accumulation was more obvious in DRR1 loss-of-function plants than in wild-type plants. These results suggest that DRR1 is involved in an ABA-independent drought stress response possibly through the mitigation of dehydration-induced proteotoxic stress.

Deubiquitinase UCHL1 Maintains Protein Homeostasis through the PSMA7-APEH-Proteasome Axis in High-grade Serous Ovarian Carcinoma.

Abstract: High-grade serous ovarian cancer (HGSOC) is characterized by chromosomal instability, DNA damage, oxidative stress, and high metabolic demand that exacerbate misfolded, unfolded, and damaged protein burden resulting in increased proteotoxicity. However, the underlying mechanisms that maintain protein homeostasis to promote HGSOC growth remain poorly understood. This study reports that the neuronal deubiquitinating enzyme, ubiquitin carboxyl-terminal hydrolase L1 (UCHL1), is overexpressed in HGSOC and maintains protein homeostasis. UCHL1 expression was markedly increased in HGSOC patient tumors and serous tubal intraepithelial carcinoma (HGSOC precursor lesions). High UCHL1 levels correlated with higher tumor grade and poor patient survival. UCHL1 inhibition reduced HGSOC cell proliferation and invasion, as well as significantly decreased the in vivo metastatic growth of ovarian cancer xenografts. Transcriptional profiling of UCHL1-silenced HGSOC cells revealed downregulation of genes implicated with proteasome activity along with upregulation of endoplasmic reticulum stress-induced genes. Reduced expression of proteasome subunit alpha 7 (PSMA7) and acylaminoacyl peptide hydrolase (APEH), upon silencing of UCHL1, resulted in a significant decrease in proteasome activity, impaired protein degradation, and abrogated HGSOC growth. Furthermore, the accumulation of polyubiquitinated proteins in the UCHL1-silenced cells led to attenuation of mTORC1 activity and protein synthesis, and induction of terminal unfolded protein response. Collectively, these results indicate that UCHL1 promotes HGSOC growth by mediating protein homeostasis through the PSMA7-APEH-proteasome axis. IMPLICATIONS: This study identifies the novel links in the proteostasis network to target protein homeostasis in HGSOC and recognizes the potential of inhibiting UCHL1 and APEH to sensitize cancer cells to proteotoxic stress in solid tumors.

Cell adaptation to aneuploidy by the environmental stress response dampens induction of the cytosolic unfolded-protein response.

Abstract: Aneuploid yeast exhibits hallmarks of proteotoxicity but does not have induced Hsf1. Here we show that the environmental stress response (ESR) is active in aneuploid cells and dampens Hsf1’s abilit...

The Heart of the Alzheimer's: A Mindful View of Heart Disease.

Abstract: Purpose of Review: This review summarizes the current evidence for the involvement of proteotoxicity and protein quality control systems defects in diseases of the central nervous and cardiovascular systems. Specifically, it presents the commonalities between the pathophysiology of protein misfolding diseases in the heart and the brain. Recent Findings: The involvement of protein homeostasis dysfunction has been for long time investigated and accepted as one of the leading pathophysiological causes of neurodegenerative diseases. In cardiovascular diseases instead the mechanistic focus had been on the primary role of Ca2+ dishomeostasis, myofilament dysfunction as well as extracellular fibrosis, whereas no attention was given to misfolding of proteins as a pathogenetic mechanism. Instead, in the recent years, several contributions have shown protein aggregates in failing hearts similar to the ones found in the brain and increasing evidence have highlighted the crucial importance that proteotoxicity exerts via pre-amyloidogenic species in cardiovascular diseases as well as the prominent role of the cellular response to misfolded protein accumulation. As a result, proteotoxicity, unfolding protein response (UPR), and ubiquitin-proteasome system (UPS) have recently been investigated as potential key pathogenic pathways and therapeutic targets for heart disease. Summary: Overall, the current knowledge summarized in this review describes how the misfolding process in the brain parallels in the heart. Understanding the folding and unfolding mechanisms involved early through studies in the heart will provide new knowledge for neurodegenerative proteinopathies and may prepare the stage for targeted and personalized interventions.

Heat shock proteins-driven stress granule dynamics: yet another avenue for cell survival

Abstract: Heat shock proteins (HSPs) are evolutionary conserved 'stress-response' proteins that facilitate cell survival against various adverse conditions. HSP-mediated cytoprotection was hitherto reported to occur principally in two ways. Firstly, HSPs interact directly or indirectly with apoptosis signaling components and suppress apoptosis. Secondly, through chaperon activity, HSPs suppress proteotoxicity and maintain protein-homeostasis. Recent studies highlight the interaction of HSPs with cytoplasmic stress granules (SGs). SGs are conserved cytoplasmic mRNPs granules that aid in cell survival under stressful conditions. We primarily aim to describe the distinct cell survival strategy mediated by HSPs as the crucial regulators of SGs assembly and disassembly. Based on the growing evidence, HSPs and associated co-chaperones act as important determinants of SG assembly, composition and dissolution. Under cellular stress, as a 'stress-coping mechanism', the formation of SGs reprograms protein translation machinery and modulates signaling pathways indispensable for cell survival. Besides their role in suppressing apoptosis, HSPs also regulate protein-homeostasis by their chaperone activity as well as by their tight regulation of SG dynamics. The intricate molecular signaling in and around the nexus of HSPs-SGs and its importance in diseases has to be unearthed. These studies have significant implications in the management of chronic diseases such as cancer and neurodegenerative diseases where SGs possess pathological functions.