The ATF6α arm of the Unfolded Protein Response mediates replicative senescence in human fibroblasts through a COX2/prostaglandin E 2 intracrine pathway

Cormenier, Johanna; Martin, Nathalie; Deslé, Julie; Salazar-Cardozo, Clara; Pourtier, Albin; Abbadie, Corinne; Pluquet, Olivier

doi:10.1016/j.mad.2017.08.003

Cited by 41 publications

(30 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cells become larger and flattened out and acquire an irregular shape. These alterations are more prominent in vitro than in vivo and appear to be caused by cytoskeletal rearrangements [ 75 , 76 ] and changes in cell membrane composition [ 77 ]. Senescent cells exhibit increased unfolded protein response (UPR), indicative of endoplasmic reticulum (ER) stress [ 76 , 77 ].…”

Section: The Senescence Phenotypementioning

confidence: 99%

Ageing, Cellular Senescence and Neurodegenerative Disease

Kritsilis

Rizou

Koutsoudaki

et al. 2018

IJMS

311

190

View full text Add to dashboard Cite

Ageing is a major risk factor for developing many neurodegenerative diseases. Cellular senescence is a homeostatic biological process that has a key role in driving ageing. There is evidence that senescent cells accumulate in the nervous system with ageing and neurodegenerative disease and may predispose a person to the appearance of a neurodegenerative condition or may aggravate its course. Research into senescence has long been hindered by its variable and cell-type specific features and the lack of a universal marker to unequivocally detect senescent cells. Recent advances in senescence markers and genetically modified animal models have boosted our knowledge on the role of cellular senescence in ageing and age-related disease. The aim now is to fully elucidate its role in neurodegeneration in order to efficiently and safely exploit cellular senescence as a therapeutic target. Here, we review evidence of cellular senescence in neurons and glial cells and we discuss its putative role in Alzheimer’s disease, Parkinson’s disease and multiple sclerosis and we provide, for the first time, evidence of senescence in neurons and glia in multiple sclerosis, using the novel GL13 lipofuscin stain as a marker of cellular senescence.

show abstract

Section: The Senescence Phenotypementioning

confidence: 99%

Ageing, Cellular Senescence and Neurodegenerative Disease

Kritsilis

Rizou

Koutsoudaki

et al. 2018

IJMS

311

190

View full text Add to dashboard Cite

show abstract

“…The silencing of ATF6α signaling could partly reverse the ER expansion and SASP of senescent cells. Recently, Cormenier et al [14] demonstrated that the activation of ATF6α maintained the senescent state of human fibroblasts by stimulating the COX2/PGE2 pathway. Most likely, ATF6α signaling triggered the prostaglandin pathway through the activation of NF-κB signaling.…”

Section: Er Stress In the Aging Processmentioning

confidence: 99%

“…ER stress is closely associated with both aging and AD pathology (see below). For instance, ER stress is connected to the generation of cellular senescence [12][13][14]. The number of senescent cells progressively increases with aging.…”

Section: Introductionmentioning

confidence: 99%

ER stress activates immunosuppressive network: implications for aging and Alzheimer’s disease

2020

View full text Add to dashboard Cite

The endoplasmic reticulum (ER) contains stress sensors which recognize the accumulation of unfolded proteins within the lumen of ER, and subsequently these transducers stimulate the unfolded protein response (UPR). The ER sensors include the IRE1, PERK, and ATF6 transducers which activate the UPR in an attempt to restore the quality of protein folding and thus maintain cellular homeostasis. If there is excessive stress, UPR signaling generates alarmins, e.g., chemokines and cytokines, which activate not only tissue-resident immune cells but also recruit myeloid and lymphoid cells into the affected tissues. ER stress is a crucial inducer of inflammation in many pathological conditions. A chronic low-grade inflammation and cellular senescence have been associated with the aging process and many age-related diseases, such as Alzheimer's disease. Currently, it is known that immune cells can exhibit great plasticity, i.e., they are able to display both pro-inflammatory and anti-inflammatory phenotypes in a context-dependent manner. The microenvironment encountered in chronic inflammatory conditions triggers a compensatory immunosuppression which defends tissues from excessive inflammation. Recent studies have revealed that chronic ER stress augments the suppressive phenotypes of immune cells, e.g., in tumors and other inflammatory disorders. The activation of immunosuppressive network, including myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg), has been involved in the aging process and Alzheimer's disease. We will examine in detail whether the ER stress-related changes found in aging tissues and Alzheimer's disease are associated with the activation of immunosuppressive network, as has been observed in tumors and many chronic inflammatory diseases.

show abstract

“…Senescent cells display changes in the organization of nuclear lamina that modify nuclear morphology and gene expression (Freund et al, 2012). Due to cytoskeletal rearrangements, senescent cells display an increased size, a flat and irregular shape and changes in cell membrane composition (Ohno-Iwashita et al, 2010;Druelle et al, 2016;Cormenier et al, 2018).…”

Section: Non-telomeric Dna Damagementioning

confidence: 99%

“…(viii) Altered proteostasis. Senescence cells display increased unfolded protein response (UPR) associated with endoplasmic reticulum (ER) stress, which participates in the increase in ER size and the changes in the shape and size of these cells (Ohno-Iwashita et al, 2010;Cormenier et al, 2018).…”

Section: Non-telomeric Dna Damagementioning

confidence: 99%

Cellular Senescence in Neurodegenerative Diseases

Martı́nez-Cué

Rueda

2020

Front. Cell. Neurosci.

191

132

View full text Add to dashboard Cite

Cellular senescence is a homeostatic biological process characterized by a permanent state of cell cycle arrest that can contribute to the decline of the regenerative potential and function of tissues. The increased presence of senescent cells in different neurodegenerative diseases suggests the contribution of senescence in the pathophysiology of these disorders. Although several factors can induce senescence, DNA damage, oxidative stress, neuroinflammation, and altered proteostasis have been shown to play a role in its onset. Oxidative stress contributes to accelerated aging and cognitive dysfunction stages affecting neurogenesis, neuronal differentiation, connectivity, and survival. During later life stages, it is implicated in the progression of cognitive decline, synapse loss, and neuronal degeneration. Also, neuroinflammation exacerbates oxidative stress, synaptic dysfunction, and neuronal death through the harmful effects of pro-inflammatory cytokines on cell proliferation and maturation. Both oxidative stress and neuroinflammation can induce DNA damage and alterations in DNA repair that, in turn, can exacerbate them. Another important feature associated with senescence is altered proteostasis. Because of the disruption in the function and balance of the proteome, senescence can modify the proper synthesis, folding, quality control, and degradation rate of proteins producing, in some diseases, misfolded proteins or aggregation of abnormal proteins. There is an extensive body of literature that associates cellular senescence with several neurodegenerative disorders including Alzheimer's disease (AD), Down syndrome (DS), and Parkinson's disease (PD). This review summarizes the evidence of the shared neuropathological events in these neurodegenerative diseases and the implication of cellular senescence in their onset or aggravation. Understanding the role that cellular senescence plays in them could help to develop new therapeutic strategies.

show abstract

The ATF6α arm of the Unfolded Protein Response mediates replicative senescence in human fibroblasts through a COX2/prostaglandin E 2 intracrine pathway

Cited by 41 publications

References 55 publications

Ageing, Cellular Senescence and Neurodegenerative Disease

Ageing, Cellular Senescence and Neurodegenerative Disease

ER stress activates immunosuppressive network: implications for aging and Alzheimer’s disease

Cellular Senescence in Neurodegenerative Diseases

Contact Info

Product

Resources

About