Gene regulatory network analysis supports inflammation as a key neurodegeneration process in prion disease.
BACKGROUND
The activation of immune cells in the brain is believed to be one of the earliest events in prion disease development, where misfolded PrionSc protein deposits are thought to act as irritants leading to a series of events that culminate in neuronal cell dysfunction and death. The role of these events in prion disease though is still a matter of debate. To elucidate the mechanisms leading from abnormal protein deposition to neuronal injury, we have performed a detailed network analysis of genes differentially expressed in several mouse prion models.


RESULTS
We found a master regulatory core of genes related to immune response controlling other genes involved in prion protein replication and accumulation, and neuronal cell death. This regulatory core determines the existence of two stable states that are consistent with the transcriptome analysis comparing prion infected versus uninfected mouse brain. An in silico perturbation analysis demonstrates that core genes are individually capable of triggering the transition and that the network remains locked once the diseased state is reached.


CONCLUSIONS
We hypothesize that this locking may be the cause of the sustained immune response observed in prion disease. Our analysis supports the hypothesis that sustained brain inflammation is the main pathogenic process leading to neuronal dysfunction and loss, which, in turn, leads to clinical symptoms in prion disease.
Luxembourg Center for Systems Biomedicine (LCSB), University of Luxembourg, Campus Belval, 7, avenue des Hauts fourneaux, Luxembourg L-4362, Luxembourg.
Isaac
I
Crespo
Kirsten
K
Roomp
Wiktor
W
Jurkowski
Hiroaki
H
Kitano
Antonio
A
del Sol
D000818:Animals; D016923:Cell Death / Q000235:genetics; D018450:Disease Progression; D053263:Gene Regulatory Networks; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D051379:Mice; D009474:Neurons / Q000473:pathology; D017096:Prion Diseases / Q000235:genetics* / Q000473:pathology; D049490:Systems Biology