The celecoxib derivatives AR-12 and AR-14 induce autophagy and clear prion-infected cells from prions

Abdulrahman, Basant; Abdelaziz, Dalia H.; Thapa, Simrika; Lü, Li; Jain, Shubha; Gilch, Sabine; Proniuk, Stefan; Zukiwski, Alexander; Schätzl, Hermann

doi:10.1038/s41598-017-17770-8

Cited by 25 publications

(26 citation statements)

References 75 publications

(71 reference statements)

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“…We compared PrP C levels in C8D astrocytes with levels in a neuronal cell line derived from the peripheral nervous system (N2a), CNS-derived CAD5 cells, and immortalized MEFs. These cells were chosen because of their excellent susceptibility to prion infection (40,70). Our results revealed that PrP C mRNA levels in C8D astrocytes were comparable with that of N2a and MEF cells but lower than CAD5 cells.…”

Section: Discussionmentioning

confidence: 72%

An astrocyte cell line that differentially propagates murine prions

Tahir

Abdulrahman

Abdelaziz

et al. 2020

Journal of Biological Chemistry

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Prion diseases are fatal infectious neurodegenerative disorders in human and animals caused by misfolding of the cellular prion protein (PrPC) into the pathological isoform PrPSc. Elucidating the molecular and cellular mechanisms underlying prion propagation may help to develop disease interventions. Cell culture systems for prion propagation have greatly advanced molecular insights into prion biology, but translation of in vitro to in vivo findings is often disappointing. A wider range of cell culture systems might help overcome these shortcomings. Here, we describe an immortalized mouse neuronal astrocyte cell line (C8D1A) that can be infected with murine prions. Both PrPC protein and mRNA levels in astrocytes were comparable to those in neuronal and nonneuronal cell lines permitting persistent prion infection. We challenged astrocytes with three mouse-adapted prion strains (22L, RML, and ME7) and cultured them for six passages. Immunoblotting results revealed that the astrocytes propagated 22L prions well over all six passages, whereas ME7 prions did not replicate, and RML prions only very weakly after five passages. Immunofluorescence analysis indicated similar results for PrPSc. Interestingly, when we used prion conversion activity as a read-out in real-time quaking-induced conversion (RT-QuIC) assays with RML-infected cell lysates, we observed a strong signal over all six passages, comparable to that for 22L-infected cells. These data indicate that the C8D1A cell line is permissive to prion infection. Moreover, the propagated prions differed in conversion and proteinase K–resistance levels in these astrocytes. We propose that the C8D1A cell line could be used to decipher prion strain biology.

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Section: Discussionmentioning

confidence: 72%

An astrocyte cell line that differentially propagates murine prions

Tahir

Abdulrahman

Abdelaziz

et al. 2020

Journal of Biological Chemistry

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“…To quantify the autophagic vacuoles, the background of images in the same series was filtered by the same threshold. Then, the “analyze particle” option of ImageJ was applied to quantify the mean fluorescence intensity, indicating the autophagy activity 18 .…”

Section: Methodsmentioning

confidence: 99%

miR-142-3p regulates autophagy by targeting ATG16L1 in thymic-derived regulatory T cell (tTreg)

Gao

Zhang

et al. 2018

Cell Death Dis

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Thymic-derived regulatory T cell (tTreg) clinical trials show therapeutic promise in the prevention of acute graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation patients. However, strategies are needed to improve tTreg proliferative ability and survival as a means to improve tTreg therapy and reduce the requirement for producing large numbers of Treg cells for adoptive tTreg transfer. Autophagy is a self-degradative process for cytosolic components, which is involved in cells death, differentiation, lymphocyte homeostasis, and tTreg function. Studies have shown that mice with tTreg cells that have a disrupted autophagy process have defective tTreg cell generation and function, resulting in autoimmune disease and failed GVHD prevention by adoptively transferred tTreg cells. We found the attenuated autophagy status during ex vivo expansion, which leads us to determine whether tTreg cell survival could be augmented by miR-142-3p, the miRNA which is highly expressed in tTreg cells and potentially targets autophagy-related protein (ATG)-1, ATG16L1. We demonstrate that miR-142-3p downregulates ATG16L1 mRNA and production of ATG16L1, that has been linked to autoimmune diseases. Conversely, miR-142-3p knock-down improved tTreg cell expansion, survival and function in vitro and vivo. In aggregate, these studies provide a new approach that uses miR-142-3p knockdown to increase tTreg cell efficacy by increasing ATG16L1 mRNA and protein and the autophagy process.

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“…In the absence of a functional UPS, the autophagosomal-lysosomal pathway is known to target insoluble protein aggregates for degradation 11 . Inducing autophagy using trehalose 12 , lithium 13 , rapamycin 8 resveratrol 14 and celecoxib derivatives AR-12 15 has shown protection against prion infectivity in in vitro model systems. Furthermore, treatment with rapamycin and resveratrol has shown delayed disease onset in in vivo prion models 8 , 14 , although the precise mechanisms remain to be determined.…”

Section: Introductionmentioning

confidence: 99%

Spermine increases acetylation of tubulins and facilitates autophagic degradation of prion aggregates

Phadwal

Kurian

Salamat

et al. 2018

Sci Rep

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Autolysosomal dysfunction and unstable microtubules are hallmarks of chronic neurodegenerative diseases associated with misfolded proteins. Investigation of impaired protein quality control and clearance systems could therefore provide an important avenue for intervention. To investigate this we have used a highly controlled model for protein aggregation, an in vitro prion system. Here we report that prion aggregates traffic via autolysosomes in the cytoplasm. Treatment with the natural polyamine spermine clears aggregates by enhancing autolysosomal flux. We demonstrated this by blocking the formation of mature autophagosomes resulting in accumulation of prion aggregates in the cytoplasm. Further we investigated the mechanism of spermine’s mode of action and we demonstrate that spermine increases the acetylation of microtubules, which is known to facilitate retrograde transport of autophagosomes from the cellular periphery to lysosomes located near the nucleus. We further report that spermine facilitates selective autophagic degradation of prion aggregates by binding to microtubule protein Tubb6. This is the first report in which spermine and the pathways regulated by it are applied as a novel approach towards clearance of misfolded prion protein and we suggest that this may have important implication for the broader family of protein misfolding diseases.

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The celecoxib derivatives AR-12 and AR-14 induce autophagy and clear prion-infected cells from prions

Cited by 25 publications

References 75 publications

An astrocyte cell line that differentially propagates murine prions

An astrocyte cell line that differentially propagates murine prions

miR-142-3p regulates autophagy by targeting ATG16L1 in thymic-derived regulatory T cell (tTreg)

Spermine increases acetylation of tubulins and facilitates autophagic degradation of prion aggregates

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