Prion propagation in mice lacking central nervous system NF-kappaB signalling.
Prions induce highly typical histopathological changes including cell death, spongiosis and activation of glia, yet the molecular pathways leading to neurodegeneration remain elusive. Following prion infection, enhanced nuclear factor-kappaB (NF-kappaB) activity in the brain parallels the first pathological changes. The NF-kappaB pathway is essential for proliferation, regulation of apoptosis and immune responses involving induction of inflammation. The IkappaB kinase (IKK) signalosome is crucial for NF-kappaB signalling, consisting of the catalytic IKKalpha/IKKbeta subunits and the regulatory IKKgamma subunit. This study investigated the impact of NF-kappaB signalling on prion disease in mouse models with a central nervous system (CNS)-restricted elimination of IKKbeta or IKKgamma in nearly all neuroectodermal cells, including neurons, astrocytes and oligodendrocytes, and in mice containing a non-phosphorylatable IKKalpha subunit (IKKalpha AA/AA). In contrast to previously published data, the observed results showed no evidence supporting the hypothesis that impaired NF-kappaB signalling in the CNS impacts on prion pathogenesis.
Julius
C
C
Institute of Neuropathology, University Hospital of Zürich, Zürich, Switzerland.
Heikenwalder
M
M
Institute of Neuropathology, University Hospital of Zürich, Zürich, Switzerland.
Schwarz
P
P
Institute of Neuropathology, University Hospital of Zürich, Zürich, Switzerland.
Marcel
A
A
Institute of Neuropathology, University Hospital of Zürich, Zürich, Switzerland.
Karin
M
M
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, USA.
Prinz
M
M
Department of Neuropathology, University of Freiburg, Freiburg, Germany.
Pasparakis
M
M
Institute for Genetics, University of Cologne, Cologne, Germany.
Aguzzi
A
A
Institute of Neuropathology, University Hospital of Zürich, Zürich, Switzerland.
D000818:Animals; D001921:Brain / Q000473:pathology; D051550:I-kappa B Kinase / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D018620:PrPSc Proteins / Q000378:metabolism* / Q000472:pathogenicity; D012608:Scrapie / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D014774:Virulence
D016328:NF-kappa B; D018620:PrPSc Proteins; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse