scholarly journals Molecular Investigation of the Unfolded Protein Response in Select Human Tauopathies

2021 ◽  
pp. 1-15
Author(s):  
Aleksandra P. Pitera ◽  
Iain J. Hartnell ◽  
Lucy Scullard ◽  
Kirsten L. Williamson ◽  
Delphine Boche ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Unfolded Protein Response ◽  
Late Stage ◽  
Protein Quality ◽  
Cellular Responses ◽  
Cortical Tissue ◽  
Unfolded Protein ◽  
Molecular Investigation ◽  
The Unfolded Protein Response ◽  
Protein Response

Background: Tauopathies are a group of neurodegenerative diseases associated with the accumulation of misfolded tau protein. The mechanisms underpinning tau-dependent proteinopathy remain to be elucidated. A protein quality control pathway within the endoplasmic reticulum, the unfolded protein response (UPR), has been suggested as a possible pathway modulating cellular responses in a range of neurodegenerative diseases, including those associated with misfolded cytosolic tau. Objective: In this study we investigated three different clinically defined tauopathies to establish whether these diseases are accompanied by the activation of UPR. Methods: We used PCR and western blotting to probe for the modulation of several reliable UPR markers in mRNA and proteins extracted from three distinct tauopathies: 20 brain samples from Alzheimer’s disease patients, 11 from Pick’s disease, and 10 from progressive supranuclear palsy. In each disease samples from these patients were compared with equal numbers of age-matched non-demented controls. Results: Our investigation showed that different markers of UPR are not changed at the late stage of any of the human tauopathies investigated. Interestingly, UPR signatures were often observed in non-demented controls. Conclusion: These data from late-stage human cortical tissue report an activation of UPR markers within the aged brain across all cohorts investigated and further support the emerging evidence that the accumulation of misfolded cytosolic tau does not drive a diseased-associated activation of UPR.

scholarly journals Ribosomal mistranslation leads to silencing of the unfolded protein response and increased mitochondrial biogenesis

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Dmitri Shcherbakov ◽  
Youjin Teo ◽  
Heithem Boukari ◽  
Adrian Cortes-Sanchon ◽  
Matilde Mantovani ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Mitochondrial Biogenesis ◽  
Protein Quality ◽  
Genetic Manipulation ◽  
Ubiquitin Proteasome System ◽  
Limiting Factor ◽  
Unfolded Protein ◽  
Comprehensive Picture ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract Translation fidelity is the limiting factor in the accuracy of gene expression. With an estimated frequency of 10−4, errors in mRNA decoding occur in a mostly stochastic manner. Little is known about the response of higher eukaryotes to chronic loss of ribosomal accuracy as per an increase in the random error rate of mRNA decoding. Here, we present a global and comprehensive picture of the cellular changes in response to translational accuracy in mammalian ribosomes impaired by genetic manipulation. In addition to affecting established protein quality control pathways, such as elevated transcript levels for cytosolic chaperones, activation of the ubiquitin-proteasome system, and translational slowdown, ribosomal mistranslation led to unexpected responses. In particular, we observed increased mitochondrial biogenesis associated with import of misfolded proteins into the mitochondria and silencing of the unfolded protein response in the endoplasmic reticulum.

scholarly journals Modulating protein quality control

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Lars Plate ◽  
Ryan J Paxman ◽  
R Luke Wiseman ◽  
Jeffery W Kelly
Keyword(s):  
Quality Control ◽  
Small Molecules ◽  
Unfolded Protein Response ◽  
Protein Misfolding ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Misfolding Diseases ◽  
Protein Response

Small molecules that modulate the unfolded protein response have the potential to treat a variety of human protein misfolding diseases.

scholarly journals Pathogenic tau does not drive activation of the unfolded protein response

2019 ◽  
Vol 294 (25) ◽  
pp. 9679-9688 ◽  
Author(s):  
Aleksandra P. Pitera ◽  
Ayodeji A. Asuni ◽  
Vincent O'Connor ◽  
Katrin Deinhardt
Keyword(s):  
Endoplasmic Reticulum ◽  
Mouse Model ◽  
Neurodegenerative Diseases ◽  
Unfolded Protein Response ◽  
Neuronal Cultures ◽  
Critical Determinant ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

The unfolded protein response (UPR) is commonly associated with a range of neurodegenerative diseases, and targeting UPR components has been suggested as a therapeutic strategy. The UPR surveys protein folding within the endoplasmic reticulum. However, many of the misfolded proteins that accumulate in neurodegeneration are localized so that they do not directly cause endoplasmic reticulum triggers that activate this pathway. Here, using a transgenic mouse model and primary cell cultures along with quantitative PCR, immunoblotting, and immunohistochemistry, we tested whether the UPR is induced in in vivo and in vitro murine models of tauopathy that are based on expression of mutant tauP301L. We found no evidence for the UPR in the rTg4510 mouse model, in which mutant tau is transgenically expressed under the control of tetracycline-controlled transactivator protein. This observation was supported by results from acute experiments in which neuronal cultures expressed mutant tau and accumulated misfolded cytoplasmic tau aggregates but exhibited no UPR activation. These results suggest that the UPR is not induced as a response to tau misfolding and aggregation despite clear evidence for progressive cellular dysfunction and degeneration. We propose that caution is needed when evaluating the implied significance of the UPR as a critical determinant across major neurodegenerative diseases.

scholarly journals Staufen 1 amplifies proapoptotic activation of the unfolded protein response

2020 ◽  
Vol 27 (10) ◽  
pp. 2942-2951 ◽  
Author(s):  
Mandi Gandelman ◽  
Warunee Dansithong ◽  
Karla P. Figueroa ◽  
Sharan Paul ◽  
Daniel R. Scoles ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Unfolded Protein Response ◽  
Cortical Neurons ◽  
Rna Binding ◽  
Binding Protein ◽  
Unfolded Protein ◽  
Functional Consequences ◽  
Exogenous Expression ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractStaufen-1 (STAU1) is an RNA-binding protein that becomes highly overabundant in numerous neurodegenerative disease models, including those carrying mutations in presenilin1 (PSEN1), microtubule-associated protein tau (MAPT), huntingtin (HTT), TAR DNA-binding protein-43 gene (TARDBP), or C9orf72. We previously reported that elevations in STAU1 determine autophagy defects and its knockdown is protective in models of several neurodegenerative diseases. Additional functional consequences of STAU1 overabundance, however, have not been investigated. We studied the role of STAU1 in the chronic activation of the unfolded protein response (UPR), a common feature among neurodegenerative diseases and often directly associated with neuronal death. Here we report that STAU1 is a novel modulator of the UPR, and is required for apoptosis induced by activation of the PERK–CHOP pathway. STAU1 levels increased in response to multiple endoplasmic reticulum (ER) stressors, and exogenous expression of STAU1 was sufficient to cause apoptosis through the PERK–CHOP pathway of the UPR. Cortical neurons and skin fibroblasts derived from Stau1−/− mice showed reduced UPR and apoptosis when challenged with thapsigargin. In fibroblasts from individuals with SCA2 or with ALS-causing TDP-43 and C9ORF72 mutations, we found highly increased STAU1 and CHOP levels in basal conditions, and STAU1 knockdown restored CHOP levels to normal. Taken together, these results show that STAU1 overabundance reduces cellular resistance to ER stress and precipitates apoptosis.

scholarly journals First Insights on the Presence of the Unfolded Protein Response in Human Spermatozoa

2019 ◽  
Vol 20 (21) ◽  
pp. 5518 ◽  
Author(s):  
Santiago ◽  
Silva ◽  
Fardilha
Keyword(s):  
Unfolded Protein Response ◽  
Protein Quality ◽  
Male Gamete ◽  
Human Sperm ◽  
Unfolded Proteins ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Related Proteins ◽  
The Impact

The unfolded protein response (UPR) is involved in protein quality control and is activated in response to several stressors. Although in testis the UPR mechanisms are well described, their presence in spermatozoa is contentious. We aimed to investigate the presence of UPR-related proteins in human sperm and the impact of oxidative stress induction in UPR activation. To identify UPR-related proteins in human sperm, a bioinformatic approach was adopted. To explore the activation of UPR, sperm were exposed to hydrogen peroxide (H2O2) and motility, vitality, and the levels of UPR-related proteins were assessed. We identified 97 UPR-related proteins in human sperm and showed, for the first time, the presence of HSF1, GADD34, and phosphorylated eIF2α. Additionally, the exposure of human sperm to H2O2 resulted in a significant decrease in sperm viability and motility and an increase in the levels of HSF1, HSP90, HSP60, HSP27, and eIF2α; all proteins involved in sensing and response to unfolded proteins. This study gave us a first insight into the presence of UPR mechanisms in the male gamete. However, the belief that sperm are devoid of transcription and translation highlight the need to clarify if these pathways are activated in sperm in the same way as in somatic cells.

scholarly journals The Unfolded Protein Response in Immune Cells as an Emerging Regulator of Neuroinflammation

2021 ◽  
Vol 13 ◽  
Author(s):  
Dominique Fernández ◽  
Antonia Geisse ◽  
Jose Ignacio Bernales ◽  
Alonso Lira ◽  
Fabiola Osorio
Keyword(s):  
Neurodegenerative Diseases ◽  
Unfolded Protein Response ◽  
Immune Cells ◽  
Immune Cell ◽  
Immune Surveillance ◽  
Potential Contribution ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
And Function ◽  
Protein Response

Immune surveillance is an essential process that safeguards the homeostasis of a healthy brain. Among the increasing diversity of immune cells present in the central nervous system (CNS), microglia have emerged as a prominent leukocyte subset with key roles in the support of brain function and in the control of neuroinflammation. In fact, impaired microglial function is associated with the development of neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). Interestingly, these pathologies are also typified by protein aggregation and proteostasis dysfunction at the level of the endoplasmic reticulum (ER). These processes trigger activation of the unfolded protein response (UPR), which is a conserved signaling network that maintains the fidelity of the cellular proteome. Remarkably, beyond its role in protein folding, the UPR has also emerged as a key regulator of the development and function of immune cells. However, despite this evidence, the contribution of the UPR to immune cell homeostasis, immune surveillance, and neuro-inflammatory processes remains largely unexplored. In this review, we discuss the potential contribution of the UPR in brain-associated immune cells in the context of neurodegenerative diseases.

Sign in / Sign up

Export Citation Format

Share Document