Transcriptome analysis reveals altered cholesterol metabolism during the neurodegeneration in mouse scrapie model.
To identify the dynamic transcriptional alterations in CNS during the development of prion disease, brains of scrapie-infected mice and age-matched, mock-inoculated controls were analyzed immediately before inoculation and at different time points post-inoculation using Affymetrix microarray technique. A total of 449 probe sets, representing 430 genes, showed differential expression between scrapie- and mock-inoculated mice over the time course. These genes could be separated into two clusters according to expression patterns: the genes in cluster 1 demonstrated lower mRNA levels in scrapie-infected brains when compared with mock-inoculated brains, whereas genes in cluster 2 showed higher mRNA levels in scrapie-infected brains. Functional analysis of differentially expressed genes revealed the most severely affected biological process: cholesterol metabolism. The expression patterns of the cholesterol-related genes indicated an inhibited cholesterol synthesis in the diseased brains. Conspicuously, a number of cluster 1 genes, including some of cholesterol-related genes, showed not only decreasing mRNA levels in scrapie-infected brains but also increasing mRNA levels in mock-inoculated brains with increasing age. Quantitative RT-PCR analysis of some cholesterol-related genes in untreated mice suggested that changes of the examined genes observed in mock-inoculated brains are mainly age related. This finding indicated a link between age-related genes and scrapie-associated neurodegeneration.
Xiang
Wei
W
Center for Neuropathology and Prion Research, Ludwig-Maximilians-University, Munich, Germany.
Hummel
Manuela
M
Mitteregger
Gerda
G
Pace
Claudia
C
Windl
Otto
O
Mansmann
Ulrich
U
Kretzschmar
Hans A
HA
D000375:Aging / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D002784:Cholesterol / Q000096:biosynthesis*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D005810:Multigene Family / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012608:Scrapie / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D015533:Transcriptional Activation / Q000235:genetics
D012333:RNA, Messenger; D002784:Cholesterol