Identification of Differentially Expressed Genes in Scrapie-Infected Mouse Brains by Using Global Gene Expression Technology

Abstract

The pathogenesis of prion diseases, a class of transmissible fatal neurodegenerative diseases in humans and animals, is still unclear. The aim of this study was to identify the differentially regulated genes that correlate with the development of prion diseases for a better understanding of their pathological mechanisms. We employed Affymetrix Mouse Expression Arrays 430A containing >22,000 transcripts and compared the global gene expression profiles from brains of mice who were intracerebrally inoculated with scrapie strains ME7 and RML with those from brains of uninfected and mock-infected mice. The microarray data were analyzed by Significance Analysis of Microarrays, revealing 121 genes whose expression increased at least twofold in both ME7-and RML-infected mouse brains, with an estimated false discovery rate of <5%. These genes encode proteins involved in proteolysis, protease inhibition, cell growth and maintenance, the immune response, signal transduction, cell adhesion, and molecular metabolism. The time course of expression generally showed up-regulation of these genes from 120 days postinoculation (dpi) for ME7-inoculated mouse brains and from 90 dpi for RML-inoculated mouse brains. The onset of elevated expression correlated temporally with the onset of PrP Sc accumulation and the activation of glia, which may have contributed to neuronal cell death. Among the differentially regulated genes reported in the present study, the emergence of genes for several cathepsins and S100 calcium binding proteins was conspicuous. These and other genes reported here may represent novel potential diagnostic and therapeutic targets for prion disease.

Involvement of Dab1 in APP processing and β-amyloid deposition in sporadic Creutzfeldt–Jakob patients

“…We thus conclude that PrP sc may affect Dab1 phosphorylation and A production. PrP sc inoculation gives rise to a wide range of molecular responses in infected brains (Xiang et al, 2004) including in oxidative stress (Choi et al, 1998;Martin et al, 2007;Yun et al, 2006), which is also described in sCJD patients (Freixes et al, 2006;Pamplona et al, 2008;Petersen et al, 2005). Indeed, sCJD patients with PrP sc type 1 and MM polymorphism at codon 129 are characterized by faster evolution and decreased life expectancy compared with PrP sc type 2 with other polymorphisms at codon 129 (Uro-Coste et al, 2008).…”

The use of non-prion biomarkers for the diagnosis of Transmissible Spongiform Encephalopathies in the live animal

“…Genes for several cathepsins and S100 protein were also evident [126]. The authors reported that elevated gene levels correlated temporarily with the onset of PrP Sc accumulation and the activation of glia, which may have contributed to neuronal cell death [126]. The above studies demonstrate the potential of genes as diagnostic markers of prion disease.…”

“…More recently, using microarray technology Xiang et al [126] identified 121 genes from brains of scrapie-infected mice whose expression was at least twice that in control animals. The genes expressed were found to encode proteins involved in several functions including proteolysis, protease inhibition, cell growth and maintenance, immune response and molecular metabolism.…”

“…The genes expressed were found to encode proteins involved in several functions including proteolysis, protease inhibition, cell growth and maintenance, immune response and molecular metabolism. Genes for several cathepsins and S100 protein were also evident [126]. The authors reported that elevated gene levels correlated temporarily with the onset of PrP Sc accumulation and the activation of glia, which may have contributed to neuronal cell death [126].…”

Finding diamonds in the rubble

“…The first application of DNA microarrays to human neurologic disease revealed gene expression abnormalities in a transgenic mouse model of Huntington's disease (HD) (15). Subsequently, gene expression abnormalities have been found in a number of neurodegenerative diseases, including AD (1), ALS (5), PD (9,10,16), prion diseases (25), frontotemporal dementia and PSP (10), and multiple sclerosis (22), suggesting that impacting the genome is another common feature of these disorders. These studies of human neurodegenerative disease reveal some general principles.…”