Gene regulatory network analysis supports inflammation as a key neurodegeneration process in prion disease

BMC Systems Biology

Antonio del Sol²  Hiroaki Kitano¹  Wiktor Jurkowski²  Kirsten Roomp²  Isaac Crespo² 

[1] The Systems Biology Institute, Tokyo, 108-0071, Japan;Luxembourg Center for Systems Biomedicine (LCSB), University of Luxembourg, Campus Belval, 7, avenue des Hauts fourneaux, Luxembourg L-4362, Luxembourg

关键词: Stable states;    Perturbation;    Gene regulatory network;    Neurodegeneration;    Inflammation;    Prion disease;   

Others  :  1143549
DOI  :  10.1186/1752-0509-6-132

 received in 2012-05-10, accepted in 2012-09-17,  发布年份 2012

【 摘 要 】

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.

【 授权许可】

   
2012 Crespo et al.; licensee BioMed Central Ltd.

【 图 表 】

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