Fundamental Research Division
The DRF at the CEA assemble approximately 6,000 scientists since January 2016.
Scientific result | Stress response | DNA | Neurodegenerative diseases
Notorious in its abnormal form, the normal prion protein is present in all mammals, although its role is unknown. A team from the CEA-IRCM has just shed some light on this.
Whereas the abnormal form of the prion protein (PrP) causes different spongiform encephalopathies (i.e. “mad cow” disease, Creutzfeldt-Jakob disease, and scrapie in sheep), the normal form is highly conserved in mammals. This suggests that it plays an essential role, particularly for neurons in which it is highly expressed. But what role does it perform? Some results suggest that it offers protection against oxidative stress and the resulting damage to DNA, but no specific targets or mechanisms of action have been revealed to date.
One team from the CEA-IRCM has obtained model rodents that lack PrP, by deletion of the gene that encodes it. They then explored their response to methyl methanesulfonate (MMS), a product with direct deleterious effects on DNA. Their results show that in “wild type” rodents, exposure to MMS triggers the overexpression of PrP and activates an enzyme called APE1, known for its central role in repairing damaged DNA. In rodents lacking PrP, the activity of APE1, initially very weak, does not increase after exposure to MMS. Their cerebral DNA furthermore shows many damaged, unrepaired sites. The researchers then confirmed these results in vitro with neuronal stem cells and neurons taken from these same animals. Cultured and exposed to MMS, the rodent cells lacking PrP show a greater level of apoptosis than cells from normal rodents. The same applies for cells coming from human cerebral tumors1, in which PrP was inhibited by the RNA interference technique2.
These results demonstrate a protective role for the normal prion protein in oxidative stress and genotoxic attacks in general, and detail the mechanism: PrP is overexpressed shortly after the beginning of stress, and accumulates in the cell nucleus where it interacts with APE1 and stimulates its DNA repair activity. This role is especially important for neurons, which live for several decades. The researchers will now study the potential protective role of PrP concerning other types of attacks to DNA (ionizing radiation, certain drugs used in chemotherapy, etc.), and for cells other than neurons. They also want to understand which signaling pathway genotoxic agents use to activate transcription of the PrP gene.
The prion protein is critical for DNA repair and cell survival after genotoxic stress | Nucleic Acids research
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