Comprehensive transcriptional profiling of prion infection in mouse models reveals networks of responsive genes.
BACKGROUND
Prion infection results in progressive neurodegeneration of the central nervous system invariably resulting in death. The pathological effects of prion diseases in the brain are morphologically well defined, such as gliosis, vacuolation, and the accumulation of disease-specific protease-resistant prion protein (PrPSc). However, the underlying molecular events that lead to the death of neurons are poorly characterised.


RESULTS
In this study cDNA microarrays were used to profile gene expression changes in the brains of two different strains of mice infected with three strains of mouse-adapted scrapie. Extensive data was collected and analyzed, from which we identified a core group of 349 prion-related genes (PRGs) that consistently showed altered expression in mouse models. Gene ontology analysis assigned many of the up-regulated genes to functional groups associated with one of the primary neuropathological features of prion diseases, astrocytosis and gliosis; protein synthesis, inflammation, cell proliferation and lipid metabolism. Using a computational tool, Ingenuity Pathway Analysis (IPA), we were able to build networks of interacting genes from the PRG list. The regulatory cytokine TGFB1, involved in modulating the inflammatory response, was identified as the outstanding interaction partner for many of the PRGs. The majority of genes expressed in neurons were down-regulated; a number of these were involved in regulatory pathways including synapse function, calcium signalling, long-term potentiation and ERK/MAPK signalling. Two down-regulated genes coding for the transcription regulators, EGR1 and CREB1, were also identified as central to interacting networks of genes; these factors are often used as markers of neuronal activity and their deregulation could be key to loss of neuronal function.


CONCLUSIONS
These data provides a comprehensive list of genes that are consistently differentially expressed in multiple scrapie infected mouse models. Building networks of interactions between these genes provides a means to understand the complex interplay in the brain during neurodegeneration. Resolving the key regulatory and signaling events that underlie prion pathogenesis will provide targets for the design of novel therapies and the elucidation of biomarkers.
Sorensen
Garrett
G
Prion Diseases Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB, R3E 3R2, Canada. Garrett_Sorensen@phac-aspc.gc.ca
Medina
Sarah
S
Parchaliuk
Debra
D
Phillipson
Clark
C
Robertson
Catherine
C
Booth
Stephanie A
SA
D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics; D004195:Disease Models, Animal; D015536:Down-Regulation; D051766:Early Growth Response Protein 1 / Q000235:genetics; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D051379:Mice; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D017096:Prion Diseases / Q000235:genetics*; D011328:Prions / Q000235:genetics / Q000472:pathogenicity; D040081:Protein Array Analysis; D014158:Transcription, Genetic
C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D011328:Prions; D020929:Mitogen-Activated Protein Kinase Kinases