Silencing of cellular prion protein (PrPC) expression by DNA-antisense oligonucleotides induces autophagy-dependent cell death in glioma cells

Barbieri, Giulia; Palumbo, Silvia; Gabrusiewicz, Konrad; Azzalin, Alberto; Marchesi, Nicoletta; Spedito, Alessandro; Biggiogera, Marco; Sbalchiero, Elena; Mazzini, Giuliano; Miracco, Clelia; Pirtoli, Luigi; Kamińska, Bożena; Comincini, Sergio

doi:10.4161/auto.7.8.15615

Cited by 49 publications

(47 citation statements)

References 40 publications

(41 reference statements)

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“…Cell stress generally upregulates autophagy to promote clearance of toxic protein aggregates, to recycle macromolecules for repair, or to maintain homeostasis. A functional link between cellular PrP and the autophagy response to cell stress has been suggested by the results of several studies (30)(31)(32). Most often, PrP is observed to protect cells by negatively regulating autophagy.…”

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confidence: 95%

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A Proautophagic Antiviral Role for the Cellular Prion Protein Identified by Infection with a Herpes Simplex Virus 1 ICP34.5 Mutant

Korom

Wylie

Wang

et al. 2013

J Virol

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The cellular prion protein (PrP) often plays a cytoprotective role by regulating autophagy in response to cell stress. The stress of infection with intracellular pathogens can stimulate autophagy, and autophagic degradation of pathogens can reduce their replication and thus help protect the infected cells. PrP also restricts replication of several viruses, but whether this activity is related to an effect on autophagy is not known. Herpes simplex virus 1 (HSV-1) effectively counteracts autophagy through binding of its ICP34.5 protein to the cellular proautophagy protein beclin-1. Autophagy can reduce replication of an HSV-1 mutant, ⌬68H, which is incapable of binding beclin-1. We found that deletion of PrP in mice complements the attenuation of ⌬68H, restoring its capacity to replicate in the central nervous system (CNS) to wild-type virus levels after intracranial or corneal infection. Cultured primary astrocytes but not neurons derived from PrP ؊/؊ mice also complemented the attenuation of ⌬68H, enabling ⌬68H to replicate at levels equivalent to wild-type virus. Ultrastructural analysis showed that normal astrocytes exhibited an increase in the number of autophagosomes after infection with ⌬68H compared with wild-type virus, but PrP ؊/؊ astrocytes failed to induce autophagy in response to ⌬68H infection. Redistribution of EGFP-LC3 into punctae occurred more frequently in normal astrocytes infected with ⌬68H than with wild-type virus, but not in PrP ؊/؊ astrocytes, corroborating the ultrastructural analysis results. Our results demonstrate that PrP is critical for inducing autophagy in astrocytes in response to HSV-1 infection and suggest that PrP positively regulates autophagy in the mouse CNS.

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confidence: 95%

“…Reintroduction of PrP retards LC3-I to LC3-II conversion, suggesting that PrP downregulates autophagosome formation. In addition, cellular PrP inhibits induction of autophagy and autophagy-dependent cell death in gliomas (30).…”

mentioning

confidence: 99%

A Proautophagic Antiviral Role for the Cellular Prion Protein Identified by Infection with a Herpes Simplex Virus 1 ICP34.5 Mutant

Korom

Wylie

Wang

et al. 2013

J Virol

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show abstract

“…34 A recent report revealed that downregulation of PrP C expression using antisense oligonucleotides targeting the PRNP transcript led to autophagydependent cell death, with the absence of markers of apoptotic cell death in human malignant glioma cell lines and nonglial tumor cells. 35 This report suggested that PrP C could directly modulate the autophagy-dependent cell death pathway.…”

Section: Introductionmentioning

confidence: 99%

Oxidative stress impairs autophagic flux in prion protein-deficient hippocampal cells

Choi

Carp

et al. 2012

Autophagy

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“…5,6 Autophagy can function as a cellular protective activity, while it can also lead to cell death in some circumstances, namely autophagic cell death (ACD) that is referred to as type II programmed cell death, in contrast to type I programmed cell death (apoptosis). 7 This double-edged sword mechanism probably affects various diseases as well as the different stages of these diseases, which subsequently results in different outcomes. An increased number of autophagosomes has been detected in a number of neurological diseases.…”

Section: Introductionmentioning

confidence: 99%

Activation of the macroautophagic system in scrapie-infected experimental animals and human genetic prion diseases

Tian

Wang

et al. 2012

Autophagy

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Silencing of cellular prion protein (PrPC) expression by DNA-antisense oligonucleotides induces autophagy-dependent cell death in glioma cells

Cited by 49 publications

References 40 publications

A Proautophagic Antiviral Role for the Cellular Prion Protein Identified by Infection with a Herpes Simplex Virus 1 ICP34.5 Mutant

A Proautophagic Antiviral Role for the Cellular Prion Protein Identified by Infection with a Herpes Simplex Virus 1 ICP34.5 Mutant

Oxidative stress impairs autophagic flux in prion protein-deficient hippocampal cells

Activation of the macroautophagic system in scrapie-infected experimental animals and human genetic prion diseases

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