The Unfolded Protein Response and Cellular Stress, Part A

The Paradox of the Unfolded Protein Response in Cancer

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The model was assembled as a series of molecular modules integrated together to form the UPR network. Kinetic parameters for the model were estimated by comparing simulations with a family of training constraints. Eight sets of western blot experiments were used as the training constraints. Using a multi-objective thermal annealing scheme, we generated an ensemble of models consistent with the western blot constraints.

Model output was compared to eleven sets of western blot studies to test the correctness of the model. Sensitivity analysis revealed that two particular modules, the UPR initiation and apoptosis modules, were the most sensitive structural elements of the model. Coupling analysis further highlighted the importance of key nodes e.

Taken together, we demonstrated that modeling could be used to understand key structural elements of UPR, despite model uncertainty.

Understanding the architecture of this stress pathway could help us understand the design principles governing other stress related networks, e. Thus, while the current study was limited to UPR, the general strategy could be extended to other stress networks relevant to human health. Log In for instructions on accessing this content. Skip to main content. Home : Conference Presentations.

Physiological/pathological ramifications of transcription factors in the unfolded protein response

Type: Conference Presentation. Recently, it was found that the activating transcription factor ATF5 plays a similar role in mitochondrial stress in mammalian cells as ATFS-1 does in C. Neurodegenerative disorders such as Alzheimer's disease AD , PD, amyotrophic lateral sclerosis ALS , and Huntington's disease HD have all distinct clinical signs band are characterized by the accumulation of misfolded and aggregated proteins Lindholm et al.

Chronic ER stress contributes to the disease pathology as shown by manipulation of UPR signals using mouse genetics or by specific compounds and drugs. Results indicate that the role of UPR in the different disorders is complex and depends on the timing, strength and nature of the specific pathological insult underlying the disease. In dopaminergic neurons degenerating in PD, XBP1 deletion produce different outcomes depending on the age of the animals and reflecting compensatory changes in UPR-regulated factors.

In an acute neuronal injury, local delivery of XBP1 was beneficial increasing cell survival and the locomotion of animals after a spinal cord lesion Valenzuela et al. The effect of XBP1 was associated with changes in the expression of brain-derived neurotrophic factor BDNF that influences neuronal plasticity and long-term potentiation.

The role of UPR in memory-related processed in brain remain an interesting avenue to explore. In ALS, spinal cord motor neurons and corticospinal motor neurons CSMNs in brain cortex undergo cell degeneration by mechanisms only partly understood. Cell stress and autophagy contributed to cell degeneration in the CSMNs pointing to novel targets for intervention. Recent data have shown that ALS and frontotemporal dementia share a major genetic risk factor related to the presence of a hexanucleotide repeat expansion in the gene, C9orf72 Renton et al.

Studies of CSMNs may give novels insights into the molecular mechanisms underlying the neuronal dysfunctions in these diseases. However, guanabenz as an adrenergic agonist causes also hypotension and therefore cannot be used in humans.

Subsequent screening led to the identification of another molecule, Sephin1 selective inhibitor of a holophosphatase that can inhibit the stress-induced phosphatase pathway and restore protein homeostasis Das et al. In vivo sephin1 was neuroprotective in the mutant SOD1-ALS mouse model, and improved behavior with no obvious adverse effects Das et al. Sephin1 also prevented demyelination in Charcot-Marie-Tooth disease model caused by mutant myelin protein zero.

INTRODUCTION

Future studies will show whether sephin1 or similar compounds may potentially be useful for treatment of ALS and other protein misfolding disorders in humans. Studies in models of HD have shown that the lack of XBP1 is neuroprotective by reducing the aggregation of mutant Huntingtin protein Htt and increasing cell survival Vidal et al. The aggregation of mutant Htt may takes place in different neuronal compartments, such as in the nucleus and the cytosol. Recently it was shown that Htt-aggregates are also present at the nuclear membrane interfering with the normal nucleocytoplasmic transport of proteins and RNA Woerner et al.

The significance of nucleocytoplasmic alterations in HD and in other protein misfolding diseases remains to be studied further.

The mechanisms for cell toxicity in AD are complex and related to changes in synaptic transmission, an altered calcium homeostasis, increased ER stress and a chronic state of neuroinflammation Mattsson et al. Together these studies indicate the involvement of specific ER signaling in AD that affects specific neurons and neuronal circuits in various brain regions in a time-dependent manner.

Prion diseases are rare neurodegenerative disorders in humans such as Creutzfeldt-Jakob disease and in animals Bovine Spongiform Encephalopathy caused by the infectious prion protein PrP; Colby and Prusiner, Mutant and misfolded PrP aggregates in brain tissue as amyloid fibrils leading to spongiform changes and loss of brain cells over time. Mounting evidence has shown that the spreading of the disease propagation occurs from cell to cell during PrP replication by misfolded PrP causing an abnormal folding of the cellular PrP Colby and Prusiner, The self-templating ability of PrP is important for cell toxicity causing an exponential increase in amyloid fibril formation that ultimately causes cell stress and death.

In PrP specific prion-like domains are present that influence protein aggregation. Prion diseases are important as models to understand the mechanisms of protein aggregation and spreading of infectious agents in neurodegenerative disorders. Recent studies using gene expression profiling have revealed changes in prion-infected mouse brain tissue including those in specific microRNAs Majer and Booth, , and in neuronal-specific genes that influence synaptic and brain functions Boese et al.

These findings may help to identify important preclinical stages and biomarkers for early diagnoses of prion diseases.

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Increased level of the excitatory amino acid glutamate is part of the pathophysiology of brain ischemia and stroke leading to the degeneration and loss of neurons excitotoxic damage in the brain. Glutamate acts via different types of glutamate receptors and thereby influences cell signaling cascades and elevates intracellular calcium in neurons. Increased ER stress is linked to brain ischemia Su and Li, and to excitotoxic injury as studied by the use of the glutamate receptor agonist, kainic acid Sokka et al.

Epilepsy is characterized by an increased electrical activity in the brain causing repetitive seizures and neuronal dysfunctions.

Protein Misfolding Disorders: A Trip into the ER

The severity and recurrence of seizures vary between patients and in most cases can be treated with drugs. This suggests that alleviation of ER stress may be beneficial in reducing neuronal degeneration in epilepsy. Studies of the role of ER stress responses in psychiatric and mental disorders are scarce. Bipolar disorder is characterized mood changes with alternating phases of depression and increase activity mania. The pathophysiology of BD is complex and the disease is associated with other mental as well as metabolic disorders Kim et al.

Recent data using patient-derived blood or cell lines s showed that the ER stress response to tunicamycin or thapsigargin is compromised in BD compared with controls So et al. Lithium is a mood stabilizer that is used in the treatment of BD. Together this suggests that ER stress and associated pathways may prove beneficial targets to consider in treatment of BD Bengesser et al.

Regarding potential ER targets in neuropsychiatric diseases the sigma-1 receptor localized in ER subdomains interacting with mitochondria and is a target for several neuroactive drugs Hashimoto, Activation of sigma-1 receptors can afford neuroprotection and modulates ER stress pathways in the brain Hyrskyluoto et al.

ER stress and the UPR

The precise roles of sigma-1 receptor and other ER resident molecules in neuropsychiatric disease warrant further studies. Photoreceptors in the retina are specialized sensory neurons for detecting light and have a high degree of metabolic activity. Human eye diseases affecting either the rods responsible for night vision or cones responsible for day-light and color vision are often caused by mutations in specific genes involved in phototransduction or in protein quality control Chan et al.

Achromatopsia is an eye disease with the prevalence of about that affects primarily cones causing color blindness and reduced vision in afflicted patients. Mutations in cyclic-nucleotide-gated ion channel proteins, governing phototransduction by cGMP, are common causes of congenital forms of achromatopsia.

Recently, mutations in ATF6 were found in patients with autosomal recessive achromatopsia, showing that normal ATF6 signaling and BiP levels are crucial for correct protein folding in the photoreceptors Kohl et al. The ATF6 mutations are of different types; present either in the luminal part of ATF6 reducing its transport or in the transcriptionally active domain interfering with its activity Chiang et al.

Future studies will increase our understanding about the role of ATF6 in achromatopsia and other eye diseases. Retinitis pigmentosa RF is a genetically heterogeneous disorder that primarily affects the rods leading to blindness.

Like in other eye diseases, including age-related macular degeneration, autophagy may contribute to the pathology Kaarniranta et al. Cataract is a common eye disorder among elderly people that can cause blindness. In cataract, the crystallins are damaged leading to misfolding and aggregation of the proteins into insoluble amyloids impairing vision. As shown recently small molecular compounds can stabilize and reduce aggregation of cryAB in in vitro assays Makley et al. These novel substances act as pharmacological chaperons and increased lens transparency in a heredity cataract mouse model.

Furthermore, they improved lens proteins solubility in human eye samples indicating that they may therefore be considered as a novel treatment for human cataracts Makley et al. Chemical chaperons can have beneficial actions in other protein misfolding disorders as well, possibly in conjunction with other treatment strategies. The prevalence of skin disorders is high and these diseases cause much of distress for the patients. In the skin disease vitiligo there is a selective damage of melanocytes making the pigment that can occur at any age.

It is though that this can be the result of an autoimmune process or caused by reactive oxidative species and subsequent ER stress mediated cell degeneration Li et al. Cultured melanocytes from vitiligo patients have enlarged ER compared with controls and vitiligo-inducing phenol compounds activate UPR strongly in these cells Toosi et al.

Psoriasis is the most common chronic inflammatory skin disease. Recently, variations in the autophagy related 16 like-1 gene were found associated with psoriasis vulgaris and palmoplantar pustulosis Douroudis et al. Many chronic human diseases are characterized by metabolic changes and activation of cell stress signaling that contribute to pathology Hotamisligil and Davis, The interactions between metabolism and stress pathways are manifold and involve nutritional signals and hormones such as insulin and controlling anabolic and catabolic pathways.

Inflammation is a major component in metabolic diseases and these are consequently named metaflammation disorders Hotamisligil and Erbay, Deregulated metabolism may also influence the immune system, and high cholesterol was shown to impair immune cells causing autoimmune diseases Ito et al. Increased cell stress and UPR are also frequent in type 2 diabetes, in lipid disorders, in obesity, and in cardiovascular diseases Hotamisligil and Davis, Increased insulin synthesis during IR leads to accumulation of misfolded insulin that further activates the UPR Han et al.

Activated JNK cascade contribute to obesity and insulin resistance by phosphorylation of the insulin receptor substrate, IRS-1 that attenuates insulin signaling Ozcan et al. In atherosclerosis, macrophages infiltrate the vessel wall and accumulate lipids and lipotoxic substances that sustain the local inflammation. The use of the chemical chaperone 4-phenyl butyric acid 4-PBA was found to mitigate ER stress and reduce the amount of atherosclerotic lesions in vivo Erbay et al. Lipid chaperones, acting as fatty acid sensors in these cells, may provide novel targets to consider for treating dyslipidemias Erbay et al.

It remains to be studied whether supplementation with PAO can be of value in treatments of lipid and other metabolic disorders in humans. Historically it was shown that heart failure is characterized by morphological changes in the ER, as a hallmark for the ER overload and ongoing stress Maron et al. In cellular models, pressure overload induces ER stress and apoptosis in cardiac myocytes Okada et al. These finding were confirmed in preclinical experiments with mice.

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