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SRP094696
Mus musculus
16 Downloadable Samples
Illumina HiSeq 2000
Description
Sporadic Creutzfeldt-Jakob disease (sCJD) is the most prevalent form of human prion disease and it is characterized by the presence of neuronal loss, spongiform degeneration, chronic inflammation and the accumulation of misfolded and pathogenic prion protein (PrPSc). The molecular mechanisms underlying these alterations are largely unknown, but the presence of intracellular neuronal calcium (Ca+2) overload, a general feature in models of prion diseases, is suggested to play a key role in prion pathogenesis. Here we describe the presence of massive regulation of Ca+2 responsive genes in sCJD brain tissue, accompanied by two Ca+2-dependent processes: endoplasmic reticulum stress and the activation of the cysteine proteases Calpains 1/2. Pathogenic Calpain activation in sCJD is linked to the cleavage of their cellular substrates, impaired autophagy and lysosomal damage, which is partially reversed by Calpain inhibition in a cellular prion model. Calpain 1 treatment enhances seeding activity of PrPSc in a prion conversion assay. Neuronal lysosomal impairment caused by Calpain over activation leads to the release of the lysosomal protease Cathepsin S that in sCJD mainly localises in axons. Additionally, massive Cathepsin S overexpression is detected in microglial cells. Alterations in Ca+2 homeostasis and activation of Calpain-Cathepsin axis already occur at pre-clinical stages of the disease as detected in a humanized sCJD mouse model. Altogether our work indicates that unbalanced Calpain-Cathepsin activation is a relevant contributor to the pathogenesis of sCJD at multiple molecular levels and a potential target for therapeutic intervention. Overall design: To identify differentially expressed genes during development of sCJD pathology we analysed the expression levels in the cortical region of tg340-PRNP129MM mice infected with sCJD MM1 brain homogenates at pre-clinical (120 dpi) and clinical (180 dpi) stages.
Publication Title
Altered Ca<sup>2+</sup> homeostasis induces Calpain-Cathepsin axis activation in sporadic Creutzfeldt-Jakob disease.
Sample Metadata Fields
Subject, Time
View Samples- Rattus norvegicus
- 6 Downloadable Samples
Affymetrix Rat Gene 2.0 ST Array (ragene20st)
Description
We identified Ncoa3 as a regulator of neuronal morphology and microRNA activity. In order to uncover target genes of this transcriptional coactivator we performed this microarray analysis.
Publication Title
A large-scale functional screen identifies Nova1 and Ncoa3 as regulators of neuronal miRNA function.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Rattus norvegicus
- 15 Downloadable Samples
- Affymetrix Rat Gene 2.1 ST Array (ragene21st)
Description
Analysis of the effects of sulphatide specific antibody (O4, 20microg/ml) on myelinating cultures generated from dissociated embryonic rat spinal cord after 24 hours treatment to give insights into effects of lipid-specific antibodies and its implication in demyelinating diseases.
Publication Title
Lipid-specific IgMs induce antiviral responses in the CNS: implications for progressive multifocal leukoencephalopathy in multiple sclerosis.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Rattus norvegicus
- 30 Downloadable Samples
- Affymetrix Rat Gene 1.0 ST Array (ragene10st)
Description
Analysis of the effects of three members of the FGF family (FGF1, FGF2 and FGF9) and bone morphogenic protein 4 (BMP4) on myelinating cultures generated from dissociated embryonic spinal cord. The results of both immediate (24 hours, T1 (24 hrs)) and long term treatments (10days, T2) give insights into the cumulative effects of sustained FGF and BMP mediated signal transduction in the pathogenesis of demyelinating diseases.
Publication Title
Fibroblast growth factor signalling in multiple sclerosis: inhibition of myelination and induction of pro-inflammatory environment by FGF9.
Sample Metadata Fields
Specimen part, Treatment, Time
View Samples- Rattus norvegicus
- 8 Downloadable Samples
- Affymetrix Rat Gene 1.0 ST Array (ragene10st)
Description
Failure of remyelination in multiple sclerosis (MS) is associated with inhibition of oligodendrocyte precursor (OPC) differentiation, but the cellular and molecular mechanisms involved remain poorly understood. We now report inflammatory demyelination in MS is associated with localized expression of fibroblast growth factor 9 (FGF9) by oligodendrocytes and to a lesser extent astrocytes, and demonstrate FGF9 inhibits myelination and remyelination in vitro. This inhibitory activity is reversible and due to an off target FGF9-dependent effect on astrocytes that disrupts in the growth factor milieu required to support myelination.
Publication Title
Fibroblast growth factor signalling in multiple sclerosis: inhibition of myelination and induction of pro-inflammatory environment by FGF9.
Sample Metadata Fields
Specimen part, Treatment, Time
View Samples