title: Genetic ablation of IP3 receptor 2 increases cytokines and decreases survival of SOD1G93A mice.
abstract: Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disease characterized by the selective death of motor neurons. Disease pathophysiology is complex and not yet fully understood. Higher gene expression of the inositol 1,4,5-trisphosphate receptor 2 gene (ITPR2), encoding the IP3receptor 2 (IP3R2), was detected in sporadic ALS patients. Here, we demonstrate that IP3R2 gene expression was also increased in spinal cords of ALS mice. Moreover, an increase of IP3R2 expression was observed in other models of chronic and acute neurodegeneration. Upregulation of IP3R2 gene expression could be induced by lipopolysaccharide (LPS) in murine astrocytes, murine macrophages and human fibroblasts indicating that it may be a compensatory response to inflammation. Preventing this response by genetic deletion of ITPR2 from SOD1G93Amice had a dose-dependent effect on disease duration, resulting in a significantly shorter lifespan of these mice. In addition, the absence of IP3R2 led to increased innate immunity, which may contribute to the decreased survival of the SOD1G93Amice. Besides systemic inflammation, IP3R2 knockout mice also had increased IFNγ, IL-6 and IL1α expression. Altogether, our data indicate that IP3R2 protects against the negative effects of inflammation, suggesting that the increase in IP3R2 expression in ALS patients is a protective response.
authors.affiliation: KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND).|VIB, Vesalius Research Center, Laboratory of Neurobiology.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Staats
authors.affiliation: VIB and Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Humblet-Baron
authors.affiliation: KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND).|VIB, Vesalius Research Center, Laboratory of Neurobiology.
authors.forename: Andre
authors.initials: A
authors.lastname: Bento-Abreu
authors.affiliation: KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND).|VIB, Vesalius Research Center, Laboratory of Neurobiology.
authors.forename: Wendy
authors.initials: W
authors.lastname: Scheveneels
authors.affiliation: Molecular and Biochemical Pharmacology Laboratory, Vrije Universiteit Brussel.|Myeloid Cell Immunology Laboratory, VIB, Inflammation Research Center.|Cellular and Molecular Immunology Unit, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Nikolaou
authors.affiliation: Center for Molecular and Vascular Biology, University of Leuven.
authors.forename: Kato
authors.initials: K
authors.lastname: Deckers
authors.affiliation: KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND).|VIB, Vesalius Research Center, Laboratory of Neurobiology.|University Hospitals Leuven, Department of Neurology.
authors.forename: Robin
authors.initials: R
authors.lastname: Lemmens
authors.affiliation: KU Leuven - University of Leuven, Department of Neurosciences, Laboratory for Neuroimmunology, Leuven, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Goris
authors.affiliation: Myeloid Cell Immunology Laboratory, VIB, Inflammation Research Center.|Cellular and Molecular Immunology Unit, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Jo A
authors.initials: JA
authors.lastname: Van Ginderachter
authors.affiliation: KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND).|VIB, Vesalius Research Center, Laboratory of Neurobiology.|University Hospitals Leuven, Department of Neurology.
authors.forename: Philip
authors.initials: P
authors.lastname: Van Damme
authors.affiliation: Laboratory for Developmental Neurobiology, Brain Science Institute, RIKEN, Wako-shi, Saitama, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Hisatsune
authors.affiliation: Laboratory for Developmental Neurobiology, Brain Science Institute, RIKEN, Wako-shi, Saitama, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Mikoshiba
authors.affiliation: VIB and Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium.
authors.forename: Adrian
authors.initials: A
authors.lastname: Liston
authors.affiliation: KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND).|VIB, Vesalius Research Center, Laboratory of Neurobiology.|University Hospitals Leuven, Department of Neurology.
authors.forename: Wim
authors.initials: W
authors.lastname: Robberecht
authors.affiliation: KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND) ludo.vandenbosch@vib-kuleuven.be.|VIB, Vesalius Research Center, Laboratory of Neurobiology.
authors.forename: Ludo
authors.initials: L
authors.lastname: Van Den Bosch
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000473:pathology; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics*; D007371:Interferon-gamma / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D000072105:Superoxide Dismutase-1 / Q000235:genetics*
chemical_list: C587672:IL1B protein, mouse; D053496:Inositol 1,4,5-Trisphosphate Receptors; D053583:Interleukin-1beta; D015850:Interleukin-6; C580990:Ip3r2 protein, mouse; D008070:Lipopolysaccharides; D007371:Interferon-gamma; C000606291:Sod1 protein, mouse; D000072105:Superoxide Dismutase-1