Gene-Expression Profiling Suggests Impaired Signaling via the Interferon Pathway in Cstb(-/-) Microglia

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http://hdl.handle.net/10138/165188

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Korber , I , Katayama , S , Einarsdottir , E , Krjutskov , K , Hakala , P , Kere , J , Lehesjoki , A-E & Joensuu , T 2016 , ' Gene-Expression Profiling Suggests Impaired Signaling via the Interferon Pathway in Cstb(-/-) Microglia ' , PLoS One , vol. 11 , no. 6 , 0158195 . https://doi.org/10.1371/journal.pone.0158195

Title: Gene-Expression Profiling Suggests Impaired Signaling via the Interferon Pathway in Cstb(-/-) Microglia
Author: Korber, Inken; Katayama, Shintaro; Einarsdottir, Elisabet; Krjutskov, Kaarel; Hakala, Paula; Kere, Juha; Lehesjoki, Anna-Elina; Joensuu, Tarja
Contributor: University of Helsinki, Research Programs Unit
University of Helsinki, Research Programs Unit
University of Helsinki, Neuroscience Center
University of Helsinki, Research Programs Unit
University of Helsinki, Neuroscience Center
University of Helsinki, Research Programs Unit
Date: 2016-06-29
Language: eng
Number of pages: 19
Belongs to series: PLoS One
ISSN: 1932-6203
URI: http://hdl.handle.net/10138/165188
Abstract: Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1, OMIM254800) is an autosomal recessive neurodegenerative disorder characterized by stimulus-sensitive and action-activated myoclonus, tonic-clonic epileptic seizures, and ataxia. Loss-of-function mutations in the gene encoding the cysteine protease inhibitor cystatin B (CSTB) underlie EPM1. The deficiency of CSTB in mice (Cstb(-/-) mice) generates a phenotype resembling the symptoms of EPM1 patients and is accompanied by microglial activation at two weeks of age and an upregulation of immune system-associated genes in the cerebellum at one month of age. To shed light on molecular pathways and processes linked to CSTB deficiency in microglia we characterized the transcriptome of cultured Cstb(-/-) mouse microglia using microarray hybridization and RNA sequencing (RNA-seq). The gene expression profiles obtained with these two techniques were in good accordance and not polarized to either pro- or anti-inflammatory status. In Cstb(-/-) microglia, altogether 184 genes were differentially expressed. Of these, 33 genes were identified by both methods. Several interferon-regulated genes were weaker expressed in Cstb(-/-) microglia compared to control. This was confirmed by quantitative real-time PCR of the transcripts Irf7 and Stat1. Subsequently, we explored the biological context of CSTB deficiency in microglia more deeply by functional enrichment and canonical pathway analysis. This uncovered a potential role for CSTB in chemotaxis, antigen-presentation, and in immune-and defense response-associated processes by altering JAK-STAT pathway signaling. These data support and expand the previously suggested involvement of inflammatory processes to the disease pathogenesis of EPM1 and connect CSTB deficiency in microglia to altered expression of interferon-regulated genes.
Subject: PROGRESSIVE MYOCLONUS EPILEPSY
UNVERRICHT-LUNDBORG-DISEASE
CENTRAL-NERVOUS-SYSTEM
CYSTATIN-B DEFICIENCY
I INTERFERONS
MOUSE MODEL
EPM1
NORMALIZATION
CELLS
BRAIN
3111 Biomedicine
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