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Series GSE90977 Query DataSets for GSE90977
Status Public on May 15, 2017
Title Altered Ca+2 homeostasis induces Calpain-Cathepsin axis activation in sCJD.
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary 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.
Contributor(s) Llorens F, Thüne K, Sirkoska B, Schmitz M, Cramm M, Gotzmann N, Tahir W, Carmona M, Andréoletti O, Michel U, Rajput A, Bonn S, P. Liberski P, Espinosa JC, Torres JM, Ferrer I, Zerr I
Citation(s) 28449707
Submission date Dec 07, 2016
Last update date May 15, 2019
Contact name Ashish Rajput
Phone +495513961173
Organization name German Center for Neurodegenerative Diseases (DZNE)
Department Research Group for Computational Systems Biology
Lab Bonn-lab
Street address Von-Siebold-Straße 3A
City Göttingen
State/province Niedersachsen
ZIP/Postal code 37075
Country Germany
Platforms (1)
GPL13112 Illumina HiSeq 2000 (Mus musculus)
Samples (16)
GSM2418613 Con120_rep1
GSM2418614 Con120_rep2
GSM2418615 Con120_rep3
BioProject PRJNA356545
SRA SRP094696

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Supplementary file Size Download File type/resource
GSE90977_RNA-seq_COMPLETE_4Con-4CJD_SETS_DEFINITIVE_log2FC_0.5.xlsx.gz 1.1 Mb (ftp)(http) XLSX
GSE90977_RNA_seq_COMPLETE_4_4_SETS_DEFINITIVE.xlsx.gz 9.5 Mb (ftp)(http) XLSX
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