Alteration of NF-κB activity leads to mitochondrial apoptosis after infection with pathological prion protein

Abstract

Nuclear factor kappa B (NF-κB) is a key regulator of the immune response, but in almost the same manner it is involved in induction of inflammation, proliferation and regulation of apoptosis. In the central nervous system activated NF-κB plays a neuroprotective role. While in some neurodegenerative disorders the role of NF-κB is well characterized, there is poor knowledge on the role of NF-κB in prion disease. We found binding but no transcriptional activity of the transcription factor in vitro. Characterizing the mechanism of cell death after infection with pathological prion protein increased caspase-9 and caspase-3 activity was detected and the lack of NF-κB activity resulted in the inability to activate target genes that usually play an important role in neuroprotection. Additionally, we investigated the role of NF-κB after prion infection of Nfkb1 ^–/–, Nfkb2 ^–/– and Bcl3 ^–/– mice and central nervous system-specific p65-deleted mice revealing an accelerated prion disease in NF-κB2- and Bcl-3-deficient mice, which is in line with a reduced neuroprotective activity in prion infection. Based on our findings, we propose a model whereby the alteration of NF-κB activity at the early stages of infection with pathological prion protein leads to neuronal cell death mediated by mitochondrial apoptosis.