MPTP administration in mice changes the ratio of splice isoforms of fosB and rgs9

Department of Cellular and Molecular Pharmacology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064, USA.
Brain Research (Impact Factor: 2.84). 12/2007; 1182(1):1-10. DOI: 10.1016/j.brainres.2007.08.080
Source: PubMed

ABSTRACT Most cases of Parkinson's disease (PD) are sporadic, suggesting an environmental influence on individuals affected by this neurodegenerative disorder. Environmental stresses often lead to changes in the regulation of splicing of pre-mRNA transcripts and this may lead to the pathogenesis of the disease. A 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/probenecid mouse model was used to examine the changes in the splicing of the fosB and rgs9 transcripts. The ratio of DeltafosB/fosB transcript was decreased in the substantia nigra and unchanged in the striatum after acute MPTP treatment. The DeltafosB/fosB transcript ratio decreased initially and then increased in the striatum of chronically MPTP-treated animals due to different degrees of reduction for the splice variants over time, whereas the ratio was unchanged in the substantia nigra. The ratio of rgs9-2/rgs9-1 transcript decreased in the substantia nigra of mice after acute MPTP treatment and increased temporarily in the striatum after chronic MPTP treatment. There was an increase in the DeltaFosB/FosB and RGS9-2/RGS9-1 protein ratios 3 weeks and 3 days post-treatment, respectively, in chronically treated mice. The data indicate that the pattern of splice isoforms of fosB and rgs9 reflects the brain's immediate and long-term responses to the physiological stress associated with Parkinsonism.

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Available from: Gloria Evelyn Meredith, Sep 25, 2015
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    • "In an MPTP mouse model, overexpression of one splice variant, ache-r, in the brain was protective, whereas overexpression of another variant, ache-s, enhanced the development of Parkinsonism [11]. In another study, the expression of splice variants of fosB and rgs9 was disrupted in the striatum and/or substantia nigra pars compacta of MPTP-treated Parkinsonian mice compared to controls [12]. "
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    ABSTRACT: Diagnosis of Parkinson' disease (PD) carries a high misdiagnosis rate due to failure to recognize atypical parkinsonian disorders (APD). Usually by the time of diagnosis greater than 60% of the neurons in the substantia nigra are dead. Therefore, early detection would be beneficial so that therapeutic intervention may be initiated early in the disease process. We used splice variant-specific microarrays to identify mRNAs whose expression is altered in peripheral blood of early-stage PD patients compared to healthy and neurodegenerative disease controls. Quantitative polymerase chain reaction assays were used to validate splice variant transcripts in independent sample sets. Here we report a PD signature used to classify blinded samples with 90% sensitivity and 94% specificity and an APD signature that resulted in a diagnosis with 95% sensitivity and 94% specificity. This study provides the first discriminant functions with coherent diagnostic signatures for PD and APD. Analysis of the PD biomarkers identified a regulatory network with nodes centered on the transcription factors HNF4A and TNF, which have been implicated in insulin regulation.
    PLoS ONE 08/2012; 7(8):e43595. DOI:10.1371/journal.pone.0043595 · 3.23 Impact Factor
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    • "Activation of PI3K/AKT induced by the lack of JNK3 | 249 2008), srebf2, which has been reported to be decreased in kainate injury (Kim and Ong 2009) and rsg9, which is altered in Parkinson's disease (Potashkin et al. 2007). The genes that were down-regulated included the following: dysf, which encodes for Dysferlin, a protein that has been found to be accumulated in the Alzheimer brain (Galvin et al. 2006), ip6k2, which is involved in cell death (Zhang and Burrows 2004; Shames and Minna 2008; Morrison et al. 2009) and En1, related to Parkinson's disease (Sgado et al. 2006). "
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    ABSTRACT: J. Neurochem. (2011) 117, 244–252. JNK3 is mainly expressed in the CNS and it plays a crucial role in neuronal death in several neurodegenerative diseases. By contrast, the isoforms JNK1 and JNK2 seem to be involved in brain development. The lack of Jnk3 confers neuroprotection, although mechanisms responsible are unknown. The present study analyzes the gene expression profile in hippocampus from mice lacking Jnk3 in comparison to wild-type mice. The microarray analysis showed that 22 genes are differentially expressed (z-score > 2 in two independent arrays) in Jnk3 null mice. Among these, we focused on pi3kcb, as it is directly related to the prosurvival phosphoinositide-3-kinase (PI3K)/AKT pathway. Results from Jnk3 null mice showed an increase in pik3cb transcript and protein, together with an increase in PI3K activity and phosphorylation of AKT. By contrast, these changes were not observed in Jnk1 null mice, which do not present neuroresistance to certain neurodegenerative insults. Therefore, our results indicate that the activation of PI3K/AKT pathway in hippocampus because of the increase in pik3cb transcription and that this mechanism is specifically related to the lack of Jnk3.
    Journal of Neurochemistry 04/2011; 117(2):244-52. DOI:10.1111/j.1471-4159.2011.07195.x · 4.28 Impact Factor
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    • "The literature contains several additional lines of evidence that splicing is affected in PD. Several studies found that the splicing of several of the key genes in PD, α-synuclein, parkin, synphilin-1, FOSB and RGS9, are affected in diseased individuals and in mouse models of the disease [54], [55], [56]. Furthermore, DJ-1, one of the genes mutated in genetic PD, has been implicated in splicing, through regulation of the splicing of tyrosine hydroxylase by the protein-associated splicing factor (PSF) [57]. "
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    ABSTRACT: Molecular studies of the human disease transcriptome typically involve a search for genes whose expression is significantly dysregulated in sick individuals compared to healthy controls. Recent studies have found that only a small number of the genes in human disease-related pathways show consistent dysregulation in sick individuals. However, those studies found that some pathway genes are affected in most sick individuals, but genes can differ among individuals. While a pathway is usually defined as a set of genes known to share a specific function, pathway boundaries are frequently difficult to assign, and methods that rely on such definition cannot discover novel pathways. Protein interaction networks can potentially be used to overcome these problems. We present DEGAS (DysrEgulated Gene set Analysis via Subnetworks), a method for identifying connected gene subnetworks significantly enriched for genes that are dysregulated in specimens of a disease. We applied DEGAS to seven human diseases and obtained statistically significant results that appear to home in on compact pathways enriched with hallmarks of the diseases. In Parkinson's disease, we provide novel evidence for involvement of mRNA splicing, cell proliferation, and the 14-3-3 complex in the disease progression. DEGAS is available as part of the MATISSE software package ( The subnetworks identified by DEGAS can provide a signature of the disease potentially useful for diagnosis, pinpoint possible pathways affected by the disease, and suggest targets for drug intervention.
    PLoS ONE 10/2010; 5(10):e13367. DOI:10.1371/journal.pone.0013367 · 3.23 Impact Factor
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