Unfolded protein response <scp>IRE1</scp>/<scp>XBP1</scp> signaling is required for healthy mammalian brain aging

Cabral‐Miranda, Felipe; Tamburini, Giovanni; Martínez, Gabriela; Ardiles, Álvaro O.; Medinas, Danilo B.; Gerakis, Yannis; Hung, Mei‐Li Diaz; Vidal, René L.; Fuentealba, Matías; Miedema, Tim; Duran‐Aniotz, Claudia; Díaz, Javier; Ibaceta-Gonzalez, Cristobal Ibaceta; Bermedo‐García, Francisca; Mujica, Paula; Adamson, Stuart; Vitangcol, Kaitlyn; Huerta, Hernán Huerta; Zhang, Xu; Nakamura, Tomohiro; Sardi, S. Pablo; Lipton, Stuart A.; Kennedy, Brian K.; Henríquez, Juan Pablo; Cárdenas, José Miguel; Plate, Lars; Palacios, Adrián; Hetz, Claudio

doi:10.15252/embj.2022111952

Cited by 21 publications

(11 citation statements)

References 91 publications

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“…In routine function, the ER stress signaling activates the unfolded protein response to reduce the volume of unfolded protein load and to help maintain normal cell function and metabolism [ 131 ]. However, chronic or extreme ER stress can trigger cell death by apoptosis and has been linked to many diseases such as cancer, diabetes, and neurodegenerative disorders [ 132 , 133 , 134 , 135 , 136 ].…”

Section: Pp Mechanisms Of Action As An Anti-cancer Agentmentioning

confidence: 99%

Pyrvinium Pamoate: Past, Present, and Future as an Anti-Cancer Drug

Schultz

2022

Biomedicines

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Pyrvinium, a lipophilic cation belonging to the cyanine dye family, has been used in the clinic as a safe and effective anthelminthic for over 70 years. Its structure, similar to some polyaminopyrimidines and mitochondrial-targeting peptoids, has been linked with mitochondrial localization and targeting. Over the past two decades, increasing evidence has emerged showing pyrvinium to be a strong anti-cancer molecule in various human cancers in vitro and in vivo. This efficacy against cancers has been attributed to diverse mechanisms of action, with the weight of evidence supporting the inhibition of mitochondrial function, the WNT pathway, and cancer stem cell renewal. Despite the overwhelming evidence demonstrating the efficacy of pyrvinium for the treatment of human cancers, pyrvinium has not yet been repurposed for the treatment of cancers. This review provides an in-depth analysis of the history of pyrvinium as a therapeutic, the rationale and data supporting its use as an anticancer agent, and the challenges associated with repurposing pyrvinium as an anti-cancer agent.

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Section: Pp Mechanisms Of Action As An Anti-cancer Agentmentioning

confidence: 99%

Pyrvinium Pamoate: Past, Present, and Future as an Anti-Cancer Drug

Schultz

2022

Biomedicines

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“…Moreover, a recent study showed that the IRE1α/XBP1 axis is required for mammalian brain aging homeostasis, as IRE1α deletion accelerated age-related cognitive decline and XBP1 overexpression reduced cell senescence and restored synaptic and cognitive function. 66 In addition, in Caenorhabditis elegans , a decline in the fidelity of protein quality control and protein homeostasis regulatory mechanisms with age causes increased ER stress levels concomitant with an accumulation of misfolded proteins. 67 , 68 Therefore, our results suggest that IRE1α is not required or its absence can be compensated for during homeostatic/normal ER stress in photoreceptors, but it is increasingly important during aging when cells experience higher levels of ER stress.…”

Section: Discussionmentioning

confidence: 99%

Deletion of the Unfolded Protein Response Transducer IRE1α Is Detrimental to Aging Photoreceptors and to ER Stress-Mediated Retinal Degeneration

Massoudi

Gorman

Kuo

et al. 2023

Invest. Ophthalmol. Vis. Sci.

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Purpose The unfolded protein response (UPR) is triggered when the protein folding capacity of the endoplasmic reticulum (ER) is overwhelmed and misfolded proteins accumulate in the ER, a condition referred to as ER stress. IRE1α is an ER-resident protein that plays major roles in orchestrating the UPR. Several lines of evidence implicate the UPR and its transducers in neurodegenerative diseases, including retinitis pigmentosa (RP), a group of inherited diseases that cause progressive dysfunction and loss of rod and cone photoreceptors. This study evaluated the contribution of IRE1α to photoreceptor development, homeostasis, and degeneration. Methods We used a conditional gene targeting strategy to selectively inactivate Ire1α in mouse rod photoreceptors. We used a combination of optical coherence tomography (OCT) imaging, histology, and electroretinography (ERG) to assess longitudinally the effect of IRE1α deficiency in retinal development and function. Furthermore, we evaluated the IRE1α-deficient retina responses to tunicamycin-induced ER stress and in the context of RP caused by the rhodopsin mutation Rho P23H . Results OCT imaging, histology, and ERG analyses did not reveal abnormalities in IRE1α-deficient retinas up to 3 months old. However, by 6 months of age, the Ire1α mutant animals showed reduced outer nuclear layer thickness and deficits in retinal function. Furthermore, conditional inactivation of Ire1α in rod photoreceptors accelerated retinal degeneration caused by the Rho P23H mutation. Conclusions These data suggest that IRE1α is dispensable for photoreceptor development but important for photoreceptor homeostasis in aging retinas and for protecting against ER stress-mediated photoreceptor degeneration.

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“…The proteasome and Xbp1 potentially provide a link to the ageing process, proteasomal activity declines with age [49] and Xbp1 has been shown to ameliorate brain ageing in mice [50] and flies [51], suggesting that a decline in their function could be a contributing factor leading to disease development with advancing age.…”

Section: Discussionmentioning

confidence: 99%

Differential neuronal vulnerability to C9orf72 repeat expansion driven by Xbp1 transcription signature

Shen,

Vincent,

Udine

et al. 2023

Preprint

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SummaryA G4C2 repeat expansion in the geneC9orf72(C9) is the most common genetic cause of sporadic and familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). What determines why cell death is triggered only in specific neuronal populations, while others remain ‘protected’ or are less susceptible to disease is still an open question. In particular, whether it is the transcriptional response to the accumulation of toxic insults or the initial cellular state that determines their vulnerability is still unknown.We have carried out a large-scale profiling of single cell transcriptional signatures throughout disease development in aDrosophilamodel of C9 repeat toxicity. This enabled us to monitor transcriptional shifts and track changes in cell populations during disease progression. We have identified neuronal populations which are depleted in response to C9 repeat expression, and therefore vulnerable to toxicity. On the other hand, other neuron types are resistant to toxicity, and maintain their cell number during disease progression. Our findings suggest that a major determinant of vulnerability is the transcriptional state of the cell before it is exposed to C9 repeat expression. We have identified a conserved transcriptional profile that is associated with resistance to C9 repeat toxicity. Neurons resistant to disease display a higher expression of genes involved in protein homeostasis, with Xbp1 identified as a crucial transcription factor determining neuronal vulnerability.

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Unfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging

Cited by 21 publications

References 91 publications

Pyrvinium Pamoate: Past, Present, and Future as an Anti-Cancer Drug

Pyrvinium Pamoate: Past, Present, and Future as an Anti-Cancer Drug

Deletion of the Unfolded Protein Response Transducer IRE1α Is Detrimental to Aging Photoreceptors and to ER Stress-Mediated Retinal Degeneration

Differential neuronal vulnerability to C9orf72 repeat expansion driven by Xbp1 transcription signature

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