Abstract
BackgroundPrion 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.ResultsIn 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.ConclusionThese 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.
Highlights
Prion infection results in progressive neurodegeneration of the central nervous system invariably resulting in death
Identification of consistently deregulated genes in mouse prion disease C57BL/6 mice were inoculated by intracerebral infection of brain homogenate from mice clinically infected with the ME7, 79a and 22A strains of scrapie
Identification of biologically relevant networks To further investigate the global expression response to infection with the prion agent, and to define how individual regulated genes interact to have a coordinated role in specific pathways, we identified potential networks of interacting prionrelated genes (PRGs)'s using the Ingenuity Pathway Analysis tool
Summary
Prion infection results in progressive neurodegeneration of the central nervous system invariably resulting in death. Brain tissue adopts a spongy appearance and a modified form of a normal host protein, the prion protein, is deposited. It is this conformational isomer of prion protein (PrPSc) that is believed to be the infectious agent. The progressive neurodegeneration resulting from infection with prion agents involves diverse cell types, a variety of cellular interactions, and multiple genes. The differential expression of these molecules between normal and diseased tissues provides information that can be used to determine the precise molecular mechanisms involved in neurodegeneration in prion disease
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