The unfolded protein response and its potential role in Huntington's disease elucidated by a systems biology approach

Huntington ́s disease (HD) is a progressive, neurodegenerative disease with a fatal outcome. Although the disease-causing gene (huntingtin) has been known for over 20 years, the exact mechanisms leading to neuronal cell death are still controversial. One potential mechanism contributing to the massive loss of neurons observed in the brain of HD patients could be the unfolded protein response (UPR) activated by accumulation of misfolded proteins in the endoplasmic reticulum (ER). As an adaptive response to counter-balance accumulation of un- or misfolded proteins, the UPR upregulates transcription of chaperones, temporarily attenuates new translation, and activates protein degradation via the proteasome. However, persistent ER stress and an activated UPR can also cause apoptotic cell death. Although different studies have indicated a role for the UPR in HD, the evidence remains inconclusive. Here, we present extensive bioinformatic analyses that revealed UPR activation in different experimental HD models based on transcriptomic data. Accordingly, we have identified 53 genes, including RAB5A, HMGB1, CTNNB1, DNM1, TUBB, TSG101, EEF2, DYNC1H1, SLC12A5, ATG5, AKT1, CASP7 and SYVN1 that provide a potential link between UPR and HD. To further elucidate the potential role of UPR as a disease-relevant process, we examined its connection to apoptosis based on molecular interaction data, and identified a set of 40 genes including ADD1, HSP90B1, IKBKB, IKBKG, RPS3A and LMNB1, which seem to be at the crossroads between these two important cellular processes. Remarkably, we also found strong correlation of UPR gene expression with the length of the polyglutamine tract of Huntingtin, which is a critical determinant of age of disease onset in human HD patients pointing to the UPR as a promising target for therapeutic intervention. The study is complemented by a newly developed web-portal called UPR-HD (http://uprhd.sysbiolab.eu) that enables visualization and interactive analysis of UPR-associated gene expression across various HD models.

Download Full-text

The unfolded protein response and its potential role in Huntington ́s disease elucidated by a systems biology approach

F1000Research ◽

10.12688/f1000research.6358.1 ◽

2015 ◽

Vol 4 ◽

pp. 103 ◽

Cited By ~ 16

Author(s):

Ravi Kiran Reddy Kalathur ◽

Joaquin Giner-Lamia ◽

Susana Machado ◽

Kameshwar R S Ayasolla ◽

Matthias E. Futschik

Keyword(s):

Cell Death ◽

Unfolded Protein Response ◽

Potential Role ◽

Apoptotic Cell ◽

Fatal Outcome ◽

Neuronal Cell ◽

Misfolded Proteins ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response

Huntington ́s disease (HD) is a progressive, neurodegenerative disease with a fatal outcome. Although the disease-causing gene (huntingtin) has been known for over 20 years, the exact mechanisms leading to neuronal cell death are still controversial. One potential mechanism contributing to the massive loss of neurons observed in the brain of HD patients could be the unfolded protein response (UPR) activated by accumulation of misfolded proteins in the endoplasmic reticulum (ER). As an adaptive response to counter-balance accumulation of un- or misfolded proteins, the UPR upregulates transcription of chaperones, temporarily attenuates new translation, and activates protein degradation via the proteasome. However, persistent ER stress and an activated UPR can also cause apoptotic cell death. Although different studies have indicated a role for the UPR in HD, the evidence remains inconclusive. Here, we present extensive bioinformatic analyses that revealed UPR activation in different experimental HD models based on transcriptomic data. Accordingly, we have identified 58 genes, including RAB5A, HMGB1, CTNNB1, DNM1, TUBB, TSG101, EEF2, DYNC1H1 and SLC12A5 that provide a potential link between UPR and HD. To further elucidate the potential role of UPR as a disease-relevant process, we examined its connection to apoptosis based on molecular interaction data, and identified a set of 40 genes including ADD1, HSP90B1, IKBKB, IKBKG, RPS3A and LMNB1, which seem to be at the crossroads between these two important cellular processes.

Download Full-text

Transcriptome Analysis of Recombinant Protein Secretion by Aspergillus nidulans and the Unfolded-Protein Response In Vivo

Applied and Environmental Microbiology ◽

10.1128/aem.71.5.2737-2747.2005 ◽

2005 ◽

Vol 71 (5) ◽

pp. 2737-2747 ◽

Cited By ~ 61

Author(s):

Andrew H. Sims ◽

Manda E. Gent ◽

Karin Lanthaler ◽

Nigel S. Dunn-Coleman ◽

Stephen G. Oliver ◽

...

Keyword(s):

Gene Expression ◽

Recombinant Protein ◽

Unfolded Protein Response ◽

Aspergillus Nidulans ◽

Filamentous Fungi ◽

Protein Secretion ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response

ABSTRACT Filamentous fungi have a high capacity for producing large amounts of secreted proteins, a property that has been exploited for commercial production of recombinant proteins. However, the secretory pathway, which is key to the production of extracellular proteins, is rather poorly characterized in filamentous fungi compared to yeast. We report the effects of recombinant protein secretion on gene expression levels in Aspergillus nidulans by directly comparing a bovine chymosin-producing strain with its parental wild-type strain in continuous culture by using expressed sequence tag microarrays. This approach demonstrated more subtle and specific changes in gene expression than those observed when mimicking the effects of protein overproduction by using a secretion blocker. The impact of overexpressing a secreted recombinant protein more closely resembles the unfolded-protein response in vivo.

Download Full-text

Enforced dimerization between XBP1s and ATF6f enhances the protective effects of the unfolded protein response (UPR) in models of neurodegeneration

10.1101/2020.11.17.387480 ◽

2020 ◽

Author(s):

René L. Vidal ◽

Denisse Sepulveda ◽

Paulina Troncoso-Escudero ◽

Paula Garcia-Huerta ◽

Constanza Gonzalez ◽

...

Keyword(s):

Gene Expression ◽

Unfolded Protein Response ◽

Target Genes ◽

Cell Function ◽

Alpha Synuclein ◽

Protective Effects ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response

AbstractAlteration to endoplasmic reticulum (ER) proteostasis is observed on a variety of neurodegenerative diseases associated with abnormal protein aggregation. Activation of the unfolded protein response (UPR) enables an adaptive reaction to recover ER proteostasis and cell function. The UPR is initiated by specialized stress sensors that engage gene expression programs through the concerted action of the transcription factors ATF4, ATF6f, and XBP1s. Although UPR signaling is generally studied as unique linear signaling branches, correlative evidence suggests that ATF6f and XBP1s may physically interact to regulate a subset of UPR-target genes. Here, we designed an ATF6f-XBP1s fusion protein termed UPRplus that behaves as a heterodimer in terms of its selective transcriptional activity. Cell-based studies demonstrated that UPRplus has stronger an effect in reducing the abnormal aggregation of mutant huntingtin and alpha-synuclein when compared to XBP1s or ATF6 alone. We developed a gene transfer approach to deliver UPRplus into the brain using adeno-associated viruses (AAVs) and demonstrated potent neuroprotection in vivo in preclinical models of Parkinson’s and Huntington’s disease. These results support the concept where directing UPR-mediated gene expression toward specific adaptive programs may serve as a possible strategy to optimize the beneficial effects of the pathway in different disease conditions.

Download Full-text

PERK/eIF2α signaling inhibits HIF-induced gene expression during the unfolded protein response via YB1-dependent regulation of HIF1α translation

Nucleic Acids Research ◽

10.1093/nar/gky127 ◽

2018 ◽

Vol 46 (8) ◽

pp. 3878-3890 ◽

Cited By ~ 11

Author(s):

Iglika G Ivanova ◽

Catherine V Park ◽

Adrian I Yemm ◽

Niall S Kenneth

Keyword(s):

Gene Expression ◽

Unfolded Protein Response ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response

Download Full-text

The Unfolded Protein Response in Immunogenic Cell Death and Cancer Immunotherapy

Trends in Cancer ◽

10.1016/j.trecan.2017.07.002 ◽

2017 ◽

Vol 3 (9) ◽

pp. 643-658 ◽

Cited By ~ 48

Author(s):

Nicole Rufo ◽

Abhishek D. Garg ◽

Patrizia Agostinis

Keyword(s):

Cell Death ◽

Unfolded Protein Response ◽

Cancer Immunotherapy ◽

Immunogenic Cell Death ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response

Download Full-text

ATM-associated signalling triggers the unfolded protein response and cell death in response to stress

Communications Biology ◽

10.1038/s42003-020-1102-2 ◽

2020 ◽

Vol 3 (1) ◽

Cited By ~ 1

Author(s):

Yuka Hotokezaka ◽

Ikuo Katayama ◽

Takashi Nakamura

Keyword(s):

Cell Death ◽

Unfolded Protein Response ◽

Unfolded Protein ◽

Response To Stress ◽

The Unfolded Protein Response ◽

Protein Response

Download Full-text

A Peptidic Unconjugated GRP78/BiP Ligand Modulates the Unfolded Protein Response and Induces Prostate Cancer Cell Death

PLoS ONE ◽

10.1371/journal.pone.0045690 ◽

2012 ◽

Vol 7 (10) ◽

pp. e45690 ◽

Cited By ~ 22

Author(s):

Danilo Maddalo ◽

Antje Neeb ◽

Katja Jehle ◽

Katja Schmitz ◽

Claudia Muhle-Goll ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Death ◽

Unfolded Protein Response ◽

Cancer Cell ◽

Prostate Cancer Cell ◽

Unfolded Protein ◽

Cancer Cell Death ◽

The Unfolded Protein Response ◽

Protein Response

Download Full-text

Nonlinear relationship between ER Ca2+ depletion versus induction of the unfolded protein response, autophagy inhibition, and cell death

Cell Calcium ◽

10.1016/j.ceca.2018.09.005 ◽

2018 ◽

Vol 76 ◽

pp. 48-61 ◽

Cited By ~ 6

Author(s):

Paula Szalai ◽

Jan B. Parys ◽

Geert Bultynck ◽

Søren Brøgger Christensen ◽

Poul Nissen ◽

...

Keyword(s):

Cell Death ◽

Unfolded Protein Response ◽

Nonlinear Relationship ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response ◽

Autophagy Inhibition

Download Full-text

Protein Misfolding Induces Hypoxic Preconditioning via a Subset of the Unfolded Protein Response Machinery

Molecular and Cellular Biology ◽

10.1128/mcb.00922-10 ◽

2010 ◽

Vol 30 (21) ◽

pp. 5033-5042 ◽

Cited By ~ 39

Author(s):

Xianrong R. Mao ◽

C. Michael Crowder

Keyword(s):

Unfolded Protein Response ◽

Protein Misfolding ◽

Transcriptional Response ◽

Hypoxic Preconditioning ◽

Misfolded Proteins ◽

Hypoxic Exposure ◽

Hypoxic Injury ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response

ABSTRACT Prolonged cellular hypoxia results in energy failure and ultimately cell death. However, less-severe hypoxia can induce a cytoprotective response termed hypoxic preconditioning (HP). The unfolded protein response pathway (UPR) has been known for some time to respond to hypoxia and regulate hypoxic sensitivity; however, the role of the UPR, if any, in HP essentially has been unexplored. We have shown previously that a sublethal hypoxic exposure of the nematode Caenorhabditis elegans induces a protein chaperone component of the UPR (L. L. Anderson, X. Mao, B. A. Scott, and C. M. Crowder, Science 323:630-633, 2009). Here, we show that HP induces the UPR and that the pharmacological induction of misfolded proteins is itself sufficient to stimulate a delayed protective response to hypoxic injury that requires the UPR pathway proteins IRE-1, XBP-1, and ATF-6. HP also required IRE-1 but not XBP-1 or ATF-6; instead, GCN-2, which is known to suppress translation and induce an adaptive transcriptional response under conditions of UPR activation or amino acid deprivation, was required for HP. The phosphorylation of the translation factor eIF2α, an established mechanism of GCN-2-mediated translational suppression, was not necessary for HP. These data suggest a model where hypoxia-induced misfolded proteins trigger the activation of IRE-1, which along with GCN-2 controls an adaptive response that is essential to HP.

Download Full-text