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Gene expression changes in the midbrain of Microcebus murinus induced by Canine adenovirus type 2 (CAV-2)

ABSTRACT: Parkinson disease (PD) is a neurodegenerative disease primarily associated with impaired movement affecting elderly people. To improve the understanding of the pathogenesis and to develop new therapies, we have developed a non-human primate model of PD using the lemurian Microcebus murinus (Mim). In this study, we tested the potential of canine adenovirus type 2 (CAV-2) as vector for gene transfer in the Mim brain by analyzing the gene expression changes in three regions involved in motor control: striatum, frontal cortex and midbrain. The CAV-2 viruses were injected in the right striatum of young adult females, 2 years old. CAV-2 vectors preferentially transduce neurons in the primate brain and were carried by axonal transport to afferent structures in both hemispheres. The gene expression changes were analyzed at 2 critical times after infection by CAV-2: an acute time effect at 24h and a delayed time effect at 28 days post infection. In addition, the gene expression was compared in the ipsilateral side versus the contralateral side, and with a non-infected brain samples using human Affymetrix microarrays. The transcriptomic data were analyzed by Significance Analysis of Microarrays (SAM) to identify genes differentially expressed when comparing brain samples in the 3 conditions. The data were also analyzed by ANOVA one way and by Principal Component Analysis (PCA). The results have shown that the transduction of CAV2 in neurons induced specific changes. These changes differed during the immediate and the long-term-point. Gene expression changes were detected in transcriptional regulation, in synaptic transmission, in cellular trafficking and in immune response. More precisely, in the short term, CAV2 activated genes involved in a non-specific innate immune response. In the long term, CAV2 induced an adaptive tolerant immune response. Gene expression changes in the midbrain of Microcebus murinus induced by Canine adenovirus type 2 (CAV-2)

ORGANISM(S): Microcebus murinus Homo sapiens

PROVIDER: GSE102709 | GEO | 2018/03/01

REPOSITORIES: GEO

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Project description:Parkinson disease (PD) is a neurodegenerative disease primarily associated with impaired movement affecting elderly people. To improve the understanding of the pathogenesis and to develop new therapies, we have developed a non-human primate model of PD using the lemurian Microcebus murinus (Mim). In this study, we tested the potential of canine adenovirus type 2 (CAV-2) as vector for gene transfer in the Mim brain by analyzing the gene expression changes in three regions involved in motor control: striatum, frontal cortex and midbrain. The CAV-2 viruses were injected in the right striatum of young adult females, 2 years old. CAV-2 vectors preferentially transduce neurons in the primate brain and were carried by axonal transport to afferent structures in both hemispheres. The gene expression changes were analyzed at 2 critical times after infection by CAV-2: an acute time effect at 24h and a delayed time effect at 28 days post infection. In addition, the gene expression was compared in the ipsilateral side versus the contralateral side, and with a non-infected brain samples using human Affymetrix microarrays. The transcriptomic data were analyzed by Significance Analysis of Microarrays (SAM) to identify genes differentially expressed when comparing brain samples in the 3 conditions. The data were also analyzed by ANOVA one way and by Principal Component Analysis (PCA). The results have shown that the transduction of CAV2 in neurons induced specific changes. These changes differed during the immediate and the long-term-point. Gene expression changes were detected in transcriptional regulation, in synaptic transmission, in cellular trafficking and in immune response. More precisely, in the short term, CAV2 activated genes involved in a non-specific innate immune response. In the long term, CAV2 induced an adaptive tolerant immune response. Gene expression changes in the frontal cortex of Microcebus murinus induced by Canine adenovirus type 2 (CAV-2)

Project description:Aging is the primary risk factor of neurodegenerative disorders such as Alzheimer's disease (AD). However, the molecular events occurring during brain aging are extremely complex and still largely unknown. For a better understanding of these age-associated modifications, animal models as close as possible to humans are needed. We thus analyzed the transcriptome of the temporal cortex of the primate Microcebus murinus using human oligonucleotide microarrays (Affymetrix). Gene expression profiles were assessed in the temporal cortex of 6 young adults, 10 healthy old animals and 2 old, "AD-like" animals that presented b-amyloid plaques and cortical atrophy, which are pathognomonic signs of AD in humans. Gene expression data of the 14,911 genes that were detected in at least 3 samples were analyzed. By SAM (significance analysis of microarrays), we identified 47 genes that discriminated young from healthy old and "AD-like" animals. These findings were confirmed by principal component analysis (PCA). ANOVA of the expression data from the three groups identified 695 genes (including the 47 genes previously identified by SAM and PCA) with significant changes of expression in old and "AD-like" in comparison to young animals. About one third of these genes showed similar changes of expression in healthy aging and in M-bM-^@M-^\AD-likeM-bM-^@M-^] animals, whereas more than two thirds showed opposite changes in these two groups in comparison to young animals. Hierarchical clustering analysis of the 695 markers indicated that each group had distinct expression profiles which characterized each group, especially the "AD-like" group. Functional categorization showed that most of the genes that were up-regulated in healthy old and down-regulated in "AD-like" animals belonged to metabolic pathways, particularly protein synthesis. These data suggest the existence of compensatory mechanisms during physiological brain aging that disappear in M-bM-^@M-^\AD-likeM-bM-^@M-^] animals. These results open the way to new exploration of physiological and M-bM-^@M-^\AD-likeM-bM-^@M-^] aging in primates. Microcebus murinus were divided in 3 groups: the first group included 6 young adults (4 females and 2 males), the second included 10 healthy old animals (7 females and 3 males) and the third one was composed by 2 "AD-like" old females. Since Microcebus murinus microarrays do not exist, we decided to use Affymetrix human genome chips (HG U133 plus 2), since studies have illustrated the feasibility of detecting non-human primate brain transcripts using human genome chips.

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Gene expression changes in the midbrain of Microcebus murinus induced by Canine adenovirus type 2 (CAV-2)

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