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

Cell Microbiol. 2007 Sep;9(9):2202-17. doi: 10.1111/j.1462-5822.2007.00950.x. Epub 2007 Jun 15.


Nuclear factor kappa B (NF-kappaB) 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-kappaB plays a neuroprotective role. While in some neurodegenerative disorders the role of NF-kappaB is well characterized, there is poor knowledge on the role of NF-kappaB 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-kappaB activity resulted in the inability to activate target genes that usually play an important role in neuroprotection. Additionally, we investigated the role of NF-kappaB after prion infection of Nfkb1(-/-), Nfkb2(-/-) and Bcl3(-/-) mice and central nervous system-specific p65-deleted mice revealing an accelerated prion disease in NF-kappaB2- 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-kappaB activity at the early stages of infection with pathological prion protein leads to neuronal cell death mediated by mitochondrial apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology
  • B-Cell Lymphoma 3 Protein
  • Brain / cytology
  • Brain / metabolism
  • Brain / pathology
  • Caspase 3 / metabolism
  • Caspase 9 / metabolism
  • Cell Line
  • Enzyme Activation
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / metabolism*
  • Molecular Sequence Data
  • NF-kappa B p50 Subunit / genetics
  • NF-kappa B p50 Subunit / metabolism*
  • NF-kappa B p52 Subunit / genetics
  • NF-kappa B p52 Subunit / metabolism*
  • PrPSc Proteins* / metabolism
  • PrPSc Proteins* / pathogenicity
  • Protein Binding
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • bcl-X Protein / genetics
  • bcl-X Protein / metabolism


  • B-Cell Lymphoma 3 Protein
  • BCL3 protein, human
  • Bcl2l1 protein, mouse
  • Bcl3 protein, mouse
  • NF-kappa B p50 Subunit
  • NF-kappa B p52 Subunit
  • Nfkb2 protein, mouse
  • PrPSc Proteins
  • Proto-Oncogene Proteins
  • Transcription Factors
  • bcl-X Protein
  • Nfkb1 protein, mouse
  • Caspase 3
  • Caspase 9