Genetic ablation of IP ₃ receptor 2 increases cytokines and decreases survival of SOD1 ^G93A 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 IP ₃ receptor 2 ( IP ₃R2 ), was detected in sporadic ALS patients. Here, we demonstrate that IP ₃R2 gene expression was also increased in spinal cords of ALS mice. Moreover, an increase of IP ₃R2 expression was observed in other models of chronic and acute neurodegeneration. Upregulation of IP ₃R2 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 SOD1 ^G93A mice had a dose-dependent effect on disease duration, resulting in a significantly shorter lifespan of these mice. In addition, the absence of IP ₃R2 led to increased innate immunity, which may contribute to the decreased survival of the SOD1 ^G93A mice. Besides systemic inflammation, IP ₃R2 knockout mice also had increased IFNγ, IL-6 and IL1α expression. Altogether, our data indicate that IP ₃R2 protects against the negative effects of inflammation, suggesting that the increase in IP ₃R2 expression in ALS patients is a protective response.